Memantine combinations and use

ABSTRACT

A pharmaceutical combination of memantine and a non-anticholinergic antiemetic agent for the treatment of hypocholinergic disorders in further combination with high doses of donepezil and with solifenacin, and kits comprising said combination. A pharmaceutical combination of memantine and solifenacin for the treatment of hypocholinergic disorders, including Alzheimer type dementia, in further combination with high doses of donepezil, and kits comprising said combination.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority benefit of U.S. Provisional PatentApplication Ser. No. 62/414,359 filed Oct. 28, 2016, U.S. ProvisionalPatent Application Ser. No. 62/424,085 filed Nov. 18, 2016, and U.S.Provisional Patent Application Ser. No. 62/423,999 filed Nov. 18, 2016;the disclosures of which are herein incorporated by reference in theirentirety.

FIELD OF THE INVENTION

This invention pertains to the field of the treatment of patientssuffering from a hypocholinergic disorder in the brain such as Alzheimerdisease, Lewy body disease, Parkinson's disease, and related disordersin humans. The invention provides a combination of memantine with anon-anticholinergic antiemetic agent (naAEA) to be safely administeredto a patient suffering from a hypocholinergic disorder in furthercombination with donepezil high doses and solifenacin, thus inducingneuroprotection in said patient. The invention also provides acombination of memantine and solifenacin to be used in furthercombination with high donepezil doses for safely improving the symptomsof hypocholinergic disorders in a patient suffering from one or more ofsaid hypocholinergic disorders and inducing neuroprotection in saidpatient, including dementia of the Alzheimer type and inducingneuroprotection in said Alzheimer type dementia patients.

Definitions

-   -   “NMDA”: N-methyl-D-aspartate    -   “ChEI(s)”: Choline Esterase Inhibitor(s).    -   “nsPAChA(s)”: non-selective, peripheral AntiCholinergic        Agent(s).    -   “Non-selective” referred to nsPAChAs, applies to anticholinergic        agents exhibiting inhibitory activity broadly across the various        subtypes of muscarinic M-receptors, namely the M1-M5 receptors,        as currently identified.    -   “Peripheral”: referred to nsPAChAs, applies to anticholinergics        that are largely unable (have a limited ability) to enter the        central nervous system following systemic administration and        thus do not affect brain function to a clinically appreciable        degree.    -   “naAEA(s)”: non-anticholinergic Anti-Emetic Agent(s).    -   “Non-anticholinergic” refers to antiemetic medications not        primarily regarded as anticholinergic agents; they are entirely        devoid of anticholinergic activity or have an extremely low        ability to prevent acetylcholine from acting at its cholinergic        receptor sites.    -   “Anticholinergic therapy”: the treatment with an anticholinergic        agent of such medical conditions as gastro-intestinal cramping,        nausea, retching, vomiting, fecal incontinence, bladder spasms,        urinary incontinence, overactive bladder, asthma, motion        sickness, muscular spasms, and smooth muscle contractive        disorders; or the treatment, if any, with an anticholinergic        agent of side effects caused by the ChEIs, including, but not        limited to gastro-intestinal cramping, nausea, retching,        vomiting, fecal incontinence, diarrhea bladder spasms, urinary        incontinence, overactive bladder.    -   “Donepezil”: the ChEI        (±)-2,3-dihydro-5,6-dimethoxy-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1H-inden-1-one.    -   “Memantine”: the NMDA-antagonist 3,5-dimethyladamantan-1-amine.    -   “Solifenacin”: the nsPAChA 1-azabicyclo[2.2.2]oct-3-yl        (1R)-1-phenyl-3,4-dihydro-1H-isoquinoline-2-carboxylate.    -   “MTD”: maximum (or maximal) tolerated dose, i.e. the highest        dose of a drug or treatment that does not cause unacceptable        side effects. The maximum tolerated dose is determined in        clinical trials by testing increasing doses on different groups        of people until the highest dose with acceptable side effects is        found (NCI Drug Dictionary).    -   “IR”: Immediate Release of the active ingredient from a        composition.    -   “ER”: Extended Release, including sustained release, modified        release, controlled release and slow release of the active        ingredient from a composition by any administration route, in        particular, but not limited to oral and parenteral (including        transcutaneous, transdermal, intramuscular, intravenous, and        subcutaneous routes).    -   “comprising” means that the compositions and methods include the        recited elements, but do not exclude others. “comprising” is        inclusive of the terms “consisting of” and “consisting        essentially of”.    -   “consisting essentially of” means that the methods and        compositions may include additional steps, components or        ingredients, but only if the additional steps, components or        ingredients do not materially alter the basic and novel        characteristics of the claimed methods and compositions. In        certain embodiments, “consisting essentially of” means that the        subsequently named component(s) is necessarily included but that        another unlisted ingredient(s) that does not materially affect        the basic and novel properties can also be present. For example,        when used to define compositions and methods, “consisting        essentially of” means excluding other elements of any essential        significance to the combination for the intended use. Thus, for        example, a composition consisting essentially of the elements as        defined herein would not exclude trace contaminants and        pharmaceutically acceptable carriers.    -   “and/or” is used herein to mean both “and” as well as “or”.    -   “pharmaceutically acceptable salt” means either a        pharmaceutically acceptable acid addition salt or a        pharmaceutically acceptable base addition salt of a currently        disclosed compound that may be administered without any        resultant substantial undesirable biological effect(s) or any        resultant deleterious interaction(s) with any other component of        a pharmaceutical composition in which it may be contained.    -   “combination therapy” means treating a patient with the        combination of the ChEI, the NMDA-antagonist and the nsPAChA as        a therapeutic platform in rotating, alternating and/or        simultaneous treatment schedules. Combination therapy may        include a temporal overlap of other therapeutic agents,        depending on the clinical course of a given hypocholinergic        disease in a subject.    -   “hypocholinergic disorder” as used herein means a clinical        disorder reflecting a deficit of acetylcholine-mediated        neurotransmission in the brain such as Alzheimer disease,        dementias of the Alzheimer-type, Lewy body dementia, Parkinson's        disease dementia, and related disorders in humans.

BACKGROUND OF THE INVENTION

The ability of memantine, a noncompetitive glutamatergic NMDA receptorantagonist of moderate affinity, to improve cognitive function in bothanimal models of human dementia and in patients with dementia of the ADtype is well established. For example, in preclinical behavioralexperiments using the water maze, this adamantane derivative (2 mg/kg)reverses scopolamine-induced learning deficits in mice (Dreyer B D,Anderson W G, Johnson H, O'Callaghan M, Seo S, Choi D Y, Riedel G, PlattB., “Memantine acts as a cholinergic stimulant in the mousehippocampus”, J Alzheimer's Dis. 2007 December; 12(4):319-33. Similarly,controlled clinical trials have demonstrated the ability of memantine tobenefit cognition in those suffering from moderate to severe forms of AD(Grossberg G T, Pejovic V, Miller M L, Graham S M, Dement “Memantinetherapy of behavioral symptoms in community-dwelling patients withmoderate to severe Alzheimer's disease”. Geriatr Cogn Disord 2009;27(2):164-172). These clinical trial results indicate that theantidementia efficacy and safety profile of memantine closely resemblethose of donepezil and other approved ChEIs. Based on these findings inpatients with moderate to severe AD, memantine has been approved forsale by regulatory authorities in the US and elsewhere for more than adecade.

More recently, memantine (usually 20 mg/day in an IR-unit form) has beenreported to enhance the antidementia efficacy of ChEIs such as standarddose—usually 10 mg/day—donepezil (Tariot P N, Farlow M R, Grossberg G T,Graham S M, McDonald S, Gergel I—Memantine Study Group, “Memantinetreatment in patients with moderate to severe Alzheimer disease alreadyreceiving donepezil: a randomized controlled trial”, JAMA 2004 Jan. 21;291(3):317-324; Atri A, Molinuevo J L, Lemming O, Wirth Y, Pulte I,Wilkinson D, “Memantine in patients with Alzheimer's disease receivingdonepezil: new analyses of efficacy and safety for combination therapy”,Alzheimers Res Ther. 2013 Jan. 21; 5(1):6). However, results from somerandomized controlled trials in patients with moderate to severe AD havefailed to show that the combination of donepezil plus memantine conferssignificant efficacy advantages over donepezil alone, regardless ofwhether donepezil was given at the standard 10 mg/day or the 23 mg/daydose (Porsteinsson A P, Grossberg G T, Mintzer J, Olin J T; MemantineMEM-MD-12 Study Group, “Memantine treatment in patients with mild tomoderate Alzheimer's disease already receiving a cholinesteraseinhibitor: a randomized, double-blind, placebo-controlled trial”, CurrAlzheimer Res. 2008 February; 5(1):83-9; Doody R S, Geldmacher D S,Farlow M R, Sun Y, Moline M, Mackell J, “Efficacy and safety ofdonepezil 23 mg versus donepezil 10 mg for moderate-to-severeAlzheimer's disease: a subgroup analysis in patients already taking ornot taking memantine”, Dement Geriatr Cogn Disord. 2012; 33(2-3):164-73;Howard R, McShane R, Lindesay J, Ritchie C, Baldwin A, Barber R, BurnsA, Dening T, Findlay D, Holmes C, Hughes A, Jacoby R, Jones R, Jones R,McKeith I, Macharouthu A, O'Brien J, Passmore P, Sheehan B, Juszczak E,Katona C, Hills R, Knapp M, Ballard C, Brown R, Banerjee S, Onions C,Griffin M, Adams J, Gray R, Johnson T, Bentham P, Phillips P, “Donepeziland memantine for moderate to severe Alzheimer's disease”, N Engl J Med.2012 Mar. 8; 366(10):893-903).

Moreover, there is no generally accepted rationale for any symptomaticbenefit gained by combining these drugs. Indeed, early on memantine wasconsidered to act as an anticholinergic and thus with the potential ofexacerbating AD symptoms (Lipton S A, Nature Reviews Drug Diiscovery2006; 5:160), while later its cognitive benefits were often linked toits well established ability to inhibit NMDA receptor mediatedglutamatergic mechanisms (Johnson J W, Glasgow N G, Povysheva N V,“Recent insights into the mode of action of memantine and ketamine”,Curr Opin Pharmacol 2015, February; 20:54-63).

Thus, to date, there is scant experimental support for this view andthus no basis to expect a synergistic or additive effect of memantine oncholinergic function. (Schmitt H P, “On the paradox of ion channelblockade and its benefits in the treatment of Alzheimer disease”, MedHypotheses. 2005; 65(2):259-65).

Conversely, it was established that the efficacy of the ChEI donepezilis improved by combining said donepezil with the nsPAChA solifenacin. Infact, for example, solifenacin is able to allow the increase up to 40mg/day of donepezil daily dose in a human being, including a patientssuffering from a dementia of Alzheimer type (Chase T N, Clarence-SmithK, “High Dose Cholinesterase Inhibitor Treatment of Alzheimer'sDisease”—AAIC Poster Abstract #27291, 2015 [PI-290], Alzheimer'sAssociation International Conference—2015, July 24-28, Washington D.C.)In addition, said donepezil dose can also be further highly increased byincreasing the dose of both solifenacin and donepezil, as illustrated inWO 2014/039627, the disclosure of which is incorporated herein in itsentirety by reference.

The action of solifenacin high doses, i.e. of solifenacin doses that areat least as high as 10 mg, but also higher and even much higher, allowfor an increase of the donepezil blood concentrations that are higherthan those attained with donepezil alone and increase even further withincreasing doses of solifenacin.

It is hereby specified that, in this disclosure and elsewhere in thescientific literature, donepezil, memantine and solifenacin are oftencited as such, i.e. as the active molecules. In the pharmaceutical andmedical field, these molecules are approved, sold, and used in form of asalt thereof, i.e. as donepezil hydrochloride, memantine hydrochlorideand, respectively, solifenacin succinate (also designated “solifenacincompound with succinic acid 1:1” and the respective doses that areeither administered in therapy or included in the respective commercialdrugs are attributed to said salts.

SUMMARY OF THE INVENTION

In a clinical investigation according to the method disclosed in WO2009/120227 (see also U.S. Pat. No. 8,404,701), the disclosures of whichare incorporated herein in their entirety by reference, donepezil andsolifenacin were administered to patients suffering from Alzheimer typedementia. A number of said patients were under treatment with memantineand entered the trial by maintaining said treatment with memantine.

It has surprisingly been found that, by treating said patients undertreatment with memantine with solifenacin and donepezil, instead of theexpected, additive synergy as previously seen when memantine was addedon to a moderately severe Alzheimer patient on a stable dose ofdonepezil, higher doses of donepezil were even more effective inpatients also taking memantine, despite the fact that the memantine doseremained constant.

This “true” synergism appears more evident when a solifenacin dose atleast as high as, but normally higher than the maximum unit form/dailysolifenacin dose used in the anticholinergic therapy is administered tomoderate/severe Alzheimer patients in a memantine/donepezil/solifenacintherapy.

Unexpectedly, it has also been found that amemantine/donepezil/solifenacin combination allows for clinicallysignificant improvement of cognitive conditions of patients sufferingfrom moderate/severe Alzheimer type dementia by using donepezil highdoses.

In particular, it has been found that moderate/severe Alzheimerpatients, who are concomitantly treated with a high dose of donepezil,the solifenacin-memantine combination induces greater improvement withsaid donepezil high-dose than those patients receiving said donepezilhigh-dose and solifenacin without concomitant memantine, where suchgreater improvement is significantly and unexpectedly greater than amere additive effect of memantine.

Thus, the present invention provides a method for the treatment ofhypocholinergic disorders, which comprises treating a patient in need ofsaid treatment with a pharmaceutical combination comprising

-   (a) an effective amount of a N-methyl-D-aspartate receptor    antagonist selected from the group consisting of memantine and    pharmaceutical acceptable salts thereof [Component (a)]; and-   (b) an effective amount of a non-selective peripheral    anticholinergic agent selected from the group consisting of    solifenacin and pharmaceutically acceptable salts thereof [Component    (b)],    in further combination with a cholinesterase inhibitor selected from    the group consisting of donepezil and pharmaceutically acceptable    salts thereof [Component (c)], at a daily dose corresponding to from    10 mg to 92 mg, preferably from 20 mg to 92 mg, normally from 10 mg    to 70 mg, preferably from 20 mg to 70 mg, of donepezil    hydrochloride.

Advantageously, said amount of memantine or of a pharmaceuticallyacceptable salt thereof is provided in a daily dose that is equivalentto from 10 mg to 30 mg of memantine hydrochloride; and said amount ofsolifenacin or of a pharmaceutically acceptable salt thereof is providedin a daily dose that is equivalent to from 10 mg to 30 mg of solifenacinsuccinate.

The present invention also provides a pharmaceutical combination, whichcomprises

-   (a) an effective amount of a NMDA-antagonist selected from the group    consisting of memantine and pharmaceutical acceptable salts thereof    [Component (a)]; and-   (b) an effective amount of a nsPAChA selected from the group    consisting of solifenacin and pharmaceutically acceptable salts    thereof [Component (b)],    for use for increasing the efficacy of a ChEI selected from the    group consisting of donepezil and pharmaceutically acceptable salts    thereof, in the treatment of hypocholinergic disorders. Said ChEI is    administered at a daily dose that is advantageously equivalent to    from 10 mg to 92 mg, preferably from 20 mg to 92 mg, normally from    10 mg to 70 mg, preferably from 20 mg to 70 mg, of donepezil    hydrochloride.

In said combination, said effective amount of memantine or of apharmaceutically acceptable salt thereof advantageously is a dose/unitform that is equivalent to from 5 mg to 30 mg of memantinehydrochloride; and said effective amount of solifenacin or of apharmaceutically acceptable salt thereof is a dose/unit form that isequivalent to from 10 mg to 30 mg of solifenacin succinate.

Said effective amount of memantine or of a pharmaceutically acceptablesalt thereof, equivalent to from 5 mg to 30 mg of memantinehydrochloride, is normally formulated in pharmaceutically compositions,preferably in dosage unit form, in admixture with a pharmaceuticalcarrier or vehicle.

Similarly, said effective amount of solifenacin or of a pharmaceuticallyacceptable salt thereof, equivalent to from 10 mg to 30 mg ofsolifenacin succinate, is normally formulated in pharmaceuticallycompositions, preferably in dosage unit form, in admixture with apharmaceutical carrier or vehicle.

Moreover, the present invention provides a memantine/solifenacinfixed-dose combination consisting of a pharmaceutical composition,preferably in dosage unit form, comprising an effective amount ofmemantine or of a pharmaceutically acceptable salt thereof and aneffective amount of solifenacin or of a pharmaceutically acceptable saltthereof, in admixture with a pharmaceutical carrier or vehicle.

Preferably, said effective amounts are equivalent to from 5 mg to 30 mgof memantine hydrochloride and, respectively to from 10 mg to 30 mg ofsolifenacin succinate.

Furthermore, the present invention provides amemantine/solifenacin/donepezil fixed-dose combination consisting of apharmaceutical composition, preferably in dosage unit form, comprisingan effective amount of memantine or of a pharmaceutically acceptablesalt thereof, an effective amount of solifenacin or of apharmaceutically acceptable salt thereof, and an effective amount ofdonepezil or of a pharmaceutically acceptable salt thereof, in admixturewith a pharmaceutical carrier or vehicle.

Advantageously, said effective amounts are, respectively, equivalent tofrom 5 mg to 30 mg, advantageously from 7 mg to 28 mg, of memantinehydrochloride; to from 10 mg to 30 mg, advantageously to from 15 mg to25 mg of solifenacin succinate; and to from 10 mg to 92 mg, preferablyfrom 20 mg to 92 mg, normally from 10 mg to 70 mg, preferably from 20 mgto 70 mg, of donepezil hydrochloride.

According to particular necessities, in particular for use in thetitration phase of the therapy, the donepezil effective amount that ispresent in the above combinations, including the fixed-dosecombinations, may be from 10 mg to 50 mg or from 40 mg to 70 mg, inparticular of 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, and 50mg.

Thus, the present invention also provides a solifenacin/donepezilfixed-dose combination consisting of a pharmaceutical composition indosage unit form, comprising from 10 mg to 30 mg, advantageously from 15mg to 25 mg, preferably of 15 mg, of solifenacin succinate and from 10mg to 92 mg, advantageously from 20 mg to 92 mg, normally from 10 mg to70 mg, preferably from 20 mg to 70 mg, of donepezil hydrochloride, inadmixture with a pharmaceutical carrier or vehicle+

Specific donepezil/solifenacin compositions comprise donepezilhydrochloride in an amount of from 10 mg to 50 mg, preferably of 10 mg,15 mg, 20 mg, 25 mg, 30 mg 35 mg, 40 mg or 50 mg, of donepezilhydrochloride wherein said solifenacin succinate and donepezilhydrochloride do not interact each other.

Finally, the present invention provides kits for an easy and safemanagement of patients in need of a memantine/solifenacin/donepeziltreatment.

It has also been found that, by treating a patient suffering from ahypocholinergic disorder, as hereinabove defined, with adonepezil/solifenacin combination, said patient concomitantly alsotaking memantine, the addition of an anticholinergic antiemetic agent tosaid memantine, especially as a memantine/naAEA fixed-dose combination,assures a safe treatment and allows for the increase of the donepezildoses without any appearance of cholinergic effects.

Thus, the present invention provides a method for the treatment ofhypocholinergic disorders, which comprises treating a patient in need ofsaid treatment with a pharmaceutical combination comprising

-   (a) an effective amount of a N-methyl-D-aspartate receptor    antagonist selected from the group consisting of memantine and    pharmaceutical acceptable salts thereof [Component (a)];-   (b) a non anticholinergic antiemetic agent (naAEA) [Component (b)];-   (c) a cholinesterase inhibitor selected from the group consisting of    donepezil and pharmaceutically acceptable salts thereof [Component    (c)], at a daily dose that is equivalent to from 10 mg to 92 mg,    preferably from 20 mg to 92 mg, normally from 10 mg to 70 mg,    preferably from 20 mg to 70 mg of donepezil hydrochloride; and-   (d) an effective amount of a non-selective peripheral    anticholinergic agent selected from the group consisting of    solifenacin and pharmaceutically acceptable salts thereof [Component    (d)];

Advantageously, said amount of memantine or of a pharmaceuticallyacceptable salt thereof is a daily dose that is equivalent to from 5 mgto 30 mg of memantine hydrochloride; and said amount of solifenacin orof a pharmaceutically acceptable salt thereof is a daily dose that isequivalent to from 10 mg to 30 mg, preferably from 15 mg to 25 mg, ofsolifenacin succinate.

Any naAEA that is an antiemetic medications commonly used to treatemesis, and not primarily regarded as anticholinergic agents, that isentirely devoid of anticholinergic activity or has an extremely lowability to prevent acetylcholine from acting at its cholinergic receptorsites in the brain may be used as Component (b) of the pharmaceuticalcombination of the present invention.

Preferably, said Component (b) is a non-anticholinergic antiemetic agentselected from the group consisting of (b1) 5HT3-antagonists, (b2)DA-antagonists, (b3) H1-antagonists, (b4) cannabinoids, and (b5)NK1-antagonists.

In said combination, said effective amount of memantine or of apharmaceutically acceptable salt thereof advantageously is a dose/unitform that is equivalent to from 5 mg to 30 mg of memantinehydrochloride; and said effective amount of solifenacin or of apharmaceutically acceptable salt thereof is a dose/unit form that isequivalent to from 10 mg to 30 mg, advantageously from 15 mg to 25 mg,of solifenacin succinate.

Said effective amount of memantine or of a pharmaceutically acceptablesalt thereof, equivalent to from 5 mg to 30 mg of memantinehydrochloride, is normally formulated in pharmaceutically compositions,preferably in dosage unit form, in admixture with a pharmaceuticalcarrier or vehicle.

Similarly, said effective amount of solifenacin or of a pharmaceuticallyacceptable salt thereof, equivalent to from 10 mg to 30 mg,advantageously from 15 mg to 25 mg, of solifenacin succinate, isnormally formulated in pharmaceutically compositions, preferably indosage unit form, in admixture with a pharmaceutical carrier or vehicle.

Also donepezil or a pharmaceutical acceptable salt thereof Component (c)is normally formulated in pharmaceutically compositions, in an amountthat is equivalent to from 10 mg to 92 mg, preferably from 20 mg to 92mg of donepezil hydrochloride, in admixture with a pharmaceuticalcarrier or vehicle.

According to particular necessities, in particular for use in thetitration phase of the therapy, the donepezil effective amount that ispresent in the above combinations, including the fixed-dosecombinations, may be from 10 mg to 50 mg, in particular of 10 mg, 15 mg,20 mg, 25 mg, 30 mg, 35 mg, 40 mg and 50 mg.

The present invention provides the above combination wherein saidComponent (a) and said Component (b) are formulated in the same unitform. Herein below, the novel (a)+(b) fixed-dose combination will alsobe designated as “Component (a/b)”. This fixed-dose combination isparticular advantageous because it allows a safe administration of highdoses of both solifenacin and donepezil and the full expression of thesynergy of solifenacin on both donepezil and memantine in patientstreated with a memantine/donepezil combination or composition.

The present invention also provides the above combination wherein saidComponents (b) and (c) are formulated in the same unit form. Hereinbelow, the (b)+(c) fixed-dose combination will also be designated as“Component (b/c)”. The naAEA/donepezil fixed doses combinations areobtainable as described in WO 2011/034568 (see also U.S. Pat. Nos.9,192,591 and 9,278,092), the contents of which are incorporated hereinin their entirety by reference.

The present invention further provides the above combination, whereinsaid Components (a) and (c) are formulated in the same unit form. Hereinbelow, the (a)+(c) fixed-dose combination will also be designated as“Component (a/c)”. This fixed dose combination is also available as abrand preparation (Namzaric®) consisting of memantine hydrochlorideextended-release/donepezil hydrochloride fixed-dose combination, when a10-mg donepezil dose is required.

In addition, any one of the Components (a), (b) and (c) of thecombination according to the present invention may be in a fixed-dosecombination with solifenacin Component (d). Herein below, saidfixed-dose combinations will be referred to as “Component (a/d)”,“Component (b/d)” and, respectively, “Component (c/d)”.

The (a)+(d) fixed-dose combination [Component (a/d)] is particularadvantageous because it has been demonstrated that solifenacin Component(d) acts synergistically in the memantine Component (a)/donepezilComponent (c) combination.

The naAEA/solifenacin fixed-dose combination Component (b/d) isexhaustively illustrated in WO 2014/039627 (see also US 2015/0231122),the contents of which are incorporated herein in their entirety byreference.

The donepezil/solifenacin fixed-dose combination Component (c/d) iscited in WO 2009/120277 (see also U.S. Pat. No. 8,404,701), the contentsof which are incorporated herein in their entirety by reference.

However, as set forth above, in the case of particular necessities,especially for use in the titration phase of the therapy, the donepezileffective amount that is present in the above fixed-dose combinations(Component (c/d/), may be from 10 mg to 50 mg, in particular of 10 mg,15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, and 50 mg.

Thus, the present invention also provides a solifenacin/donepezil (c/d)fixed-dose combination consisting of a pharmaceutical composition,preferably in dosage unit form, comprising from 10 mg to 30 mg,advantageously from 15 mg to 25 mg, preferably 15 mg, of solifenacinsuccinate and from 10 mg to 92 mg, advantageously from 20 mg to 92 mg,normally from 10 mg to 70 mg, preferably from 20 mg to 70 mg ofdonepezil hydrochloride, in admixture with a pharmaceutical carrier.Specific donepezil/solifenacin compositions comprise donepezilhydrochloride in an amount of from 10 mg to 50 mg, preferably of 10 mg,15 mg, 20 mg, 25 mg, 30 mg 35 mg or 40 mg, of donepezil hydrochloridewherein said solifenacin succinate and donepezil hydrochloride do notinteract each other.

Components (a), (b), (c) and (d) may also be combined in a triplefixed-dose combination, herein below designated as (b/c/d), (a/c/d),(a/b/d) and (a/b/c) fixed-dose combinations or in a (a/b/c/d) fixed-dosecombination.

In fact, the present inventors found that, in order to assure safetreatment of Alzheimer type dementia and sure synergy with solifenacinComponent (c), the non-anticholinergic antiemetic agent Component (b)must be administered concurrently with the memantine Component (a) andthe donepezil Component (c) from the beginning of the therapeutictreatment of a patient submitted to this treatment for the first time.In order to assure said safe treatment, said naAEA Component (b) andsaid solifenacin Component (d) are preferably present in saidcombination as a fixed-dose combination consisting of a pharmaceuticalcomposition wherein said naAEA and said solifenacin are formulated in adosage unit form in admixture with a pharmaceutical carrier, asdisclosed for example in WO 2014/039627 (see also U.S. Pat. No.9,192,591).

Finally, the present invention provides kits for an easy and safemanagement of patients in need of a memantine/donepezil/solifenacintreatment, in particular a kit wherein the Components (a), (b), (c) and(d), each alone or in double or triple fixe-dose combination.

These kits, which contain donepezil or a pharmaceutically acceptablesalt thereof, in a pharmaceutical composition in dosage unit formwherein said ChEI is in admixture with a pharmaceutical carrier, cansimplify the administration of the above combination to patientssuffering from hypocholinergic disorders of the CNS, who are often notsufficiently able to manage multiple packages.

Advantageously, the effective amounts are, respectively, equivalent tofrom 5 mg to 30 mg, preferably from 7 mg to 28 mg, of memantinehydrochloride; to from 10 mg to 30 mg, advantageously from 15 mg to 25mg, preferably 15 mg, of solifenacin succinate; and from 10 mg to 92 mg,preferably from 20 mg to 92 mg, normally from 10 mg to 70 mg, preferablyfrom 20 mg to 70 mg mg of donepezil hydrochloride.

As mentioned above, according to particular necessities, the donepezileffective amount that is present in the above combinations, includingthe fixed-dose combinations, may be of from 10 mg to 50 mg, inparticular of 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg or 40 mg.

DETAILED DESCRIPTION

The present invention provides a new tool for the treatment ofhypocholinergic disorders that is based on the fact that, by treating apatient suffering from said disorder with memantine and a naAEA, theaddition of donepezil high doses and solifenacin to this therapy allowsthe induction by solifenacin of a full synergism towards both donepeziland memantine.

The addition of an antiemetic assures a safe expression of said synergy.

The present invention also provides a new tool for the treatment ofhypocholinergic disorders that is based on the fact that, by allowingthe safe increase of the donepezil dose, solifenacin allows a fullsynergism between donepezil and memantine.

A study in patients with AD-type dementia has shown a greaterimprovement in patients receiving memantine/solifenacin/donepezil thanin those receiving donepezil/solifenacin and where such greaterimprovement is greater than a mere additive effect of memantine. In thisstudy, improvement in cognition was judged versus baseline, at a timewhen patients were either on or off memantine and continued to receivethe same dose of memantine for the duration of the trial. By contrast,the dose of donepezil was titrated up to Maximum Tolerated Dose. It wastherefore expected that any further increase in efficacy would have beenbe attributable only to the higher doses of donepezil. There shouldtherefore have been no difference in improvement between high dosedonepezil with memantine or without memantine. Yet, patients who wereconcomitantly treated with memantine had greater improvement with highdoses of donepezil than patients receiving high doses of donepezilwithout concomitant memantine, i.e, the effect of the high dose ofdonepezil itself was amplified by memantine, thus showing that thememantine/solifenacin combination is a new tool for the safe treatmentof Alzheimer type dementia. This study is described in more detail inExample 1 below.

The present invention provides a combination of memantine or apharmaceutically acceptable salt thereof (especially its hydrochloride),with solifenacin (especially its succinate) or a pharmaceuticallyacceptable salt thereof, donepezil or a pharmaceutically acceptable saltthereof (especially its hydrochloride), and a non-anticholinergicantiemetic agent that will provide improved treatment of hypocholinergicdisorders such as Alzheimer type dementia.

The present invention provides a pharmaceutical combination comprising,as Components,

-   (a) memantine or a pharmaceutically acceptable salt thereof; and-   (b) solifenacin or a pharmaceutically acceptable salt thereof.

The present invention also provides a combination of memantine or apharmaceutically acceptable salt thereof (especially its hydrochloride)Component (a), with a non-anticholinergic antiemetic agent Component(b), to be used in further combination with donepezil or apharmaceutically acceptable salt thereof (especially its hydrochloride)Component (c), and solifenacin or a pharmaceutically acceptable saltthereof (especially its succinate) Component (d), to provide improvedtreatment of hypocholinergic disorders such as Alzheimer type dementia.

These combinations include fixed-dose combinations, in particular aComponent (a)/Component (b) fixed dose combination essentiallyconsisting of a pharmaceutical composition in dosage unit formcomprising

-   (a) memantine or a pharmaceutically acceptable salt thereof, in an    amount that is equivalent to from 5 mg to 30 mg of memantine    hydrochloride; and-   (b) a non-anticholinergic antiemetic agent, in admixture with a    pharmaceutical carrier or vehicle.

This composition is useful because it compels the concurrentadministration of a memantine/antiemetic combination assuring a safetreatment of said patient suffering from said hypocholinergic disorderwith the donepezil Component (c), even at high and very high doses, andthe solifenacin Component (d); and also because it renders saidadministration of a quadruple combination more comfortable.

Component (c) and Component (d) may also be in a fixed-dosecombinations, that allows the administration of the two componentstogether in a composition to be administered once per day, thus alsocontributing in rendering the treatment more comfortable for both thepatient and the caregiver.

For the same purpose, the combination according to the present inventionis packaged in kits.

The memantine Component (a)

Memantine hydrochloride, which can be prepared for example as describedin U.S. Pat. No. 3,391,142, the disclosure of which is incorporatedherein in its entirety by reference, is a known NMDA-antagonistextensively used in the treatment of neurodegenerative disorders.Memantine and its pharmaceutically acceptable salts, such as thehydrochloride or the sulfate, alone or in combination withcholinesterase inhibitors, in particular with donepezil andpharmaceutically acceptable salts thereof, is disclosed for example inUS 2014/0050784 and in US 2004/0087658, the disclosure of which isincorporated herein in its entirety by reference.

Memantine may be administered as a brand product, in particular, as itshydrochloride or sulfate salt, in tablets for oral immediate-releaseform or in capsules oral extended release form, or as oral disintegrabletablets, for example as described in EP 2905019, the disclosure of whichis incorporated herein in its entirety by reference. Memantine can alsobe administered by a percutaneous system such as transdermal patch, asdescribed in WO 2014/174564 and WO 2014/199455, the disclosures of whichare incorporated herein in their entirety by reference, or by injectionin a long-acting preparation containing its pamoate salt (N Mittapellyet al. “Investigation of salt formation between memantine and pamoicacid”, Eur J Pharm Biopharm, 2016. April; 101, 62-71—see also U.S. Pat.No. 9,353,059 and US 2016/0310411, the disclosures of which areincorporated herein in their entirety by reference).

According to the present invention, memantine or pharmaceuticallyacceptable salts thereof is present in the combination in an amount offrom 5 mg to 30 mg and is administered to a patient at a daily dose thatis equivalent to from 10 mg to 30 mg.

A memantine/donepezil fixed-dose (a/c) combination, known as Namzaric®,may also be used according to the present invention.

According to the present invention, memantine or pharmaceuticallyacceptable salts thereof Component (a) is present in the combination inan amount of from 5 mg to 30 mg, preferably from 7 mg to 28 mg, and isadministered to a patient at a daily dose that is equivalent to from 7mg to 28 mg.

The naAEA Component (b)

Antiemetic medications commonly used to treat emesis, and not primarilyregarded as anticholinergic agents, that are entirely devoid ofanticholinergic activity or have an extremely low ability to preventacetylcholine from acting at its cholinergic receptor sites in the brainmay be used as Component (b) of the pharmaceutical combination of thepresent invention.

Preferably, said Component (b) is a non-anticholinergic antiemetic agentselected from the group consisting of (b1) 5HT3-antagonists, (b2)DA-antagonists, (b3) H1-antagonists, (b4) cannabinoids, and (b5)NK1-antagonists.

Typical non-anticholinergic antiemetic agents are

-   -   5-HT3 receptor antagonists (5HT3-antagonists), such as        9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-1,2,3,9-tetrahydrocarbazol-4-one        (ondansetron) and pharmaceutically acceptable salts and solvates        thereof, in particular its hydrochloride dihydrate, described in        EP 191562, the disclosure of which is incorporated herein in its        entirety by reference; 3S-ondansetron; 3R-onsdansetron;        (3R)-10-oxo-8-azatricyclo[5.3.1.03,8]undec-5-yl        1H-indole-3-carboxylate (dolasetron) and pharmaceutically        acceptable salts and solvates thereof, in particular its        monomethanesulfonate (mesylate or mesilate) monohydrate,        described in EP 266730;        1-methyl-N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-indazole-3-carboxamide        (granisetron) and pharmaceutically acceptable salts and solvates        thereof, in particular its hydrochloride, described in EP        200444; [(1S,5S)-8-methyl-8-azabicyclo        [3.2.1]oct-3-yl]1H-indole-3-carboxylate (tropisetron) and        pharmaceutically acceptable salts and solvates thereof, in        particular its monohydrochloride, described in U.S. Pat. No.        4,789,673, the disclosure of which is incorporated herein in its        entirety by reference;        1-phenylmethyl-2-piperazinyl-1H-benzimidazole (lerisetron) and        pharmaceutically acceptable salts and solvates thereof, in        particular its hydrochloride, described in EP 512939, the        disclosure of which is incorporated herein in its entirety by        reference;        (R)-5-[(1-methyl-3-indolyl)carbonyl]-4,5,6,7-tetrahydro-1H-benzimidazole        (ramosetron) and pharmaceutically acceptable salts and solvates        thereof, in particular its hydrochloride, described in U.S. Pat.        No. 5,344,927, the disclosure of which is incorporated herein in        its entirety by reference;        (3aR)-2-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-2,3,3a,4,5,6-hexahydro-1H-benz[de]isoquinolin-1-one        (palonosetron) and pharmaceutically acceptable salts and        solvates thereof, in particular its hydrochloride, described in        U.S. Pat. No. 5,202,333, the disclosure of which is incorporated        herein in its entirety by reference;        2,3,4,5-tetrahydro-5-methyl-2-[(5-methyl-1H-imidazol-4-yl)methyl]-1H-pyrido        [4,3-b]indol-1-one (alosetron) and pharmaceutically acceptable        salts and solvates thereof, in particular its hydrochloride,        described in U.S. Pat. No. 5,360,800, the disclosure of which is        incorporated herein in its entirety by reference; and        (±)-6-chloro-,3,4-dihydro-4-methyl-3-oxo-N-(quinuclidinyl)-2H-1,4-benzoxazine-8-carboxamide        (azasetron) and pharmaceutically acceptable salts and solvates        thereof, in particular its hydrochloride, described in U.S. Pat.        No. 4,892,872, the disclosure of which is incorporated herein in        its entirety by reference; which are known to be serotonin        receptors blockers in the central nervous system and        gastrointestinal tract and have been proposed for use to treat        post-operative and cytotoxic drug nausea and vomiting;    -   dopamine antagonists (“DA-antagonists”), such as        5-chloro-1-(1-[3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl]piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one        (domperidone) and pharmaceutically acceptable salts and solvates        thereof, particularly its maleate;        1-[1-[4-(4-fluorophenyl)-4-oxo-butyl]-3,6-dihydro-2H-pyridin-4-yl]-3H-benzoimidazol-2-one        (droperidol);        4-[4-(4-chlorophenyl)-4-hydroxy-1-piperidyl]-1-(4-fluorophenyl)-butan-1-one        (haloperidol);        3-(2-chloro-10H-phenothiazin-10-yl)-N,N-dimethyl-propan-1-amine        (chlorpromazine) and pharmaceutically acceptable salts and        solvates thereof, particularly its hydrochloride;        2-chloro-10-[3-(4-methyl-1-piperazinyl)propyl]-10H-phenothiazine        (prochlorperazine), and pharmaceutically acceptable salts and        solvates thereof, particularly its dimaleate, dimesylate or        1,2-ethanedisulfonate (1:1) (edisilate);        dimethyl[1-(10H-phenothiazin-10-yl)propan-2-yl]amine        (promethazine) and pharmaceutically acceptable salts and        solvates thereof, particularly its hydrochloride;        4-aminosalicylamide and benzamide derivatives like        4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-methoxybenzamide        (metoclopramide) and pharmaceutically acceptable salts and        solvates thereof such as its monohydrochloride monohydrate;        4-amino-5-bromo-N-[2-(diethylamino)ethyl]-2-methoxybenzamide        (bromopride) and pharmaceutically acceptable salts and solvates        thereof, particularly its monohydrochloride and its        dihydrochloride monohydrate;        4-amino-N-(1-benzylpiperidin-4-yl)-5-chloro-2-methoxybenzamide        (clebopride) and pharmaceutically acceptable salts and solvates        thereof, particularly its malate or its hydrochloride        monohydrate;        N-[(1-allylpyrrolidin-2-yl)methyl]-6-methoxy-1H-benzo[d][1,2,3]triazole-5-carboxamide        (alizapride) and pharmaceutically acceptable salts and solvates        thereof, particularly its hydrochloride;        (L)-2-methoxy-N-((1-propylpyrrolidin-2-yl)methyl)-5-sulfamoylbenzamide        (levosulpiride);        N-{[4-(2-dimethylaminoethoxy)phenyl]methyl}-3,4,5-trimethoxy-benzamide        (trimethobenzamide) and pharmaceutically acceptable salts and        solvates thereof, particularly its hydrochloride;    -   which act in the brain and especially at the chemoreceptor        trigger zone and are known to be used to treat nausea and        vomiting associated with neoplastic disease, radiation sickness,        opioids, cytotoxic drugs and general anesthetics;    -   H1 histamine receptor antagonists (“H1-antagonists”), such as        1-[(4-chlorophenyl)-phenyl-methyl]-4-[(3-methylphenyl)methyl]piperazine        (meclizine or meclozine) and pharmaceutically acceptable salts        and solvates thereof, particularly its dihydrochloride        monohydrate;        dimethyl[1-(10H-phenothiazin-10-yl)propan-2-yl]amine        (promethazine) and pharmaceutically acceptable salts and        solvates thereof, particularly its hydrochloride;        3-(2-chloro-10H-phenothiazin-10-yl)-N,N-dimethyl-propan-1-amine        (chlorpromazine) or a salt thereof, particularly its        hydrochloride;        2-chloro-10-[3-(4-methyl-1-piperazinyl)propyl]-10H-phenothiazine        (prochlorperazine) and pharmaceutically acceptable salts and        solvates thereof, particularly its dimaleate, dimesylate or        1,2-ethanedisulfonate (1:1) (edisilate); and        2-(2-{4-[(4-chlorophenyl)(phenyl)methyl]piperazin-1-yl}ethoxy)ethanol        (hydroxyzine) and pharmaceutically acceptable salts and solvates        thereof such as its hydrochloride or        1,1′-methylene-bis(2-hydroxy-3-naphthalenecarboxylic acid salt        (pamoate),    -   which are known to be effective in many conditions, including        motion sickness and severe morning sickness in pregnancy;    -   cannabinoid receptor agonists (“cannabinoids”), such as        cannabis;        (6aR-trans)-6a,7,8,10a-tetrahydro-6,6,9-trimethyl-3-pentyl-6H-dibenzo        [b,d]pyran-1-ol (dronabinol);        (6aR,10aR)-rel-3-(1,1-dimethylheptyl)-6,6a,7,8,10,10a-hexahydro-1-hydroxy,        6,6-dimethyl-9H-dibenzo[b,d]pyran-9-one (nabilone); and        (−)-cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)-phenyl]-trans-4-(3-hydroxypropyl)cyclohexanol        (CP 55,940);    -   which are known to be used in patients with cachexia and        cytotoxic nausea and vomiting; and    -   antagonists of the neurokinin 1 receptor (NK1-antagonists) such        as        5-[[(2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)-4-morpholinyl]methyl]-1,2-dihydro-3H-1,2,4-triazol-3-one        (aprepitant);        (2S,4S)-4-(4-Acetyl-1-piperazinyl)-N-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl]-2-(4-fluoro-2-methylphenyl)-N-methyl-1-piperidinecarboxamide        (casopitant);        2-[3,5-bis(trifluoromethyl)phenyl]-N,2-dimethyl-N-[4-(2-methylphenyl)-6-(4-methyl-1-piperazinyl)-3-pyridinyl]propanamide        (netupitant) described in U.S. Pat. Nos. 6,297,375, 6,719,996        and 6,593,47; the disclosures of which are incorporated herein        in their entirety; and        (5S,8S)-8-({(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}methyl)-8-phenyl-1,7-diazaspiro[4.5]decan-2-one        (rolapitant), described in U.S. Pat. No. 7,049,320 and, for an        injectable form thereof, in U.S. Pat. No. 9,101,615, the        disclosures of which are incorporated herein in their entirety        by reference; the disclosures of which are incorporated herein        in their entirety; which are known to be neurokinine-1 receptors        blockers in both the central and peripheral nervous system and        have been proposed for use to treat cytotoxic drug nausea and        vomiting.

Advantageous naAEAs are the compounds available in drugs for currentantiemetic therapy, in particular,

-   -   alosetron hydrochloride, available at the oral dose/unit form        (in alosetron) of 0.5-1 mg;    -   azasetron hydrochloride or mesilate monohydrate, available at        the oral or i.v. dose/unit form of 10 mg;    -   dolasetron mesylate monohydrate, available at the oral dose/unit        form (in dolasetron) of 50-100 mg;    -   granisetron hydrochloride, available at the oral dose (in        granisetron) of 1-2 mg or in a 52 cm² transdermal patch        containing 34.3 mg of granisetron releasing 3.1 mg of        granisetron per 24 hours (herein below indicated as 23.1 mg/24        h”;    -   ondansetron hydrochloride dihydrate, available at the oral dose        (in ondansetron) of 4-8 mg;    -   palonosetron hydrochloride, available at a the oral dose (in        palonosetron) of 0.5 mg and i.v. dose (in palonosetron) of 0.25        mg;    -   tropisetron hydrochloride, available at the oral dose (in        tropisetron) of 5 mg;    -   domperidone, available at the dose of 10 mg;    -   haloperidol, available at the oral dose of 1-10 mg;    -   chlorpromazine hydrochloride, available at the oral dose (in        chlorpromazine) of 25-100 mg;    -   prochlorperazine dimaleate, available at the oral dose of 5 mg;    -   metoclopramide hydrochloride dihydrate, available at the oral        dose (in metoclopramide) of 10 mg;    -   bromopride dihydrochloride monohydrate, available at the oral        dose (in bromopride) of 10 mg;    -   clebopride malate (1:1), available at a oral dose (in        clebopride) of 1 mg;    -   levosulpiride, at the oral dose of 25-100 mg;    -   alizapride hydrochloride, available at the oral dose (in        alizapride) of 50 mg;    -   trimethobenzamide hydrochloride, available at the oral dose (in        trimethobenzamide) of 100 mg    -   meclizine (also called meclozine), available at the oral dose of        12.5-50 mg;    -   promethazine hydrochloride, available at the oral dose (in        promethazine) of 25 mg;    -   dronabinol, available at the oral dose of 0.5-1 mg;    -   aprepitant, available at the oral dose of 40-125 mg;    -   netupitant, available at the oral dose of 300 mg; and    -   casopitant, at the oral dose of 50 mg;    -   rolapitant, available at the oral dose of 60 mg;    -   the palonosetron-0.5 mg/netupitant-300 mg oral fixed-dose        combination.

In the pharmaceutical combination to improve the treatment of humandementias of the Alzheimer type according to the present invention, thenon-anticholinergic antiemetic agent Component (b) is formulated in apharmaceutical composition in admixture with a pharmaceutical carrier tobe administered in combination with the memantine Component (a), thensPAChA component (d) and the donepezil Component (c).

The Component (b) is advantageously selected from the group consistingof alosetron and pharmaceutically acceptable salts and solvates thereof,especially its hydrochloride; azasetron and pharmaceutically acceptablesalts and solvates thereof, especially its hydrochloride; ondansetronand pharmaceutically acceptable salts and solvates thereof, especiallyits monohydrochloride dihydrate; granisetron and pharmaceuticallyacceptable salts and solvates thereof, especially its hydrochloride;dolasetron and pharmaceutically acceptable salts and solvates thereof,especially its monomethanesulfonate monohydrate, ramosetron andpharmaceutically acceptable salts and solvates thereof, especially itshydrochloride; tropisetron and pharmaceutically acceptable salts andsolvates thereof, especially its hydrochloride; palonosetron andpharmaceutically acceptable salts and solvates thereof, especially itshydrochloride; domperidone and pharmaceutically acceptable salts andsolvates thereof, especially its maleate; chlorpromazine andpharmaceutically acceptable salts and solvates thereof, especially itshydrochloride; prochlorperazine and its salts and solvates, especiallyits dimaleate and dimesylate; promethazine and pharmaceuticallyacceptable salts and solvates thereof, especially its hydrochloride;metoclopramide and pharmaceutically acceptable salts and solvatesthereof, especially its hydrochloride monohydrate; bromopride andpharmaceutically acceptable salts and solvates thereof, especially itsmonohydrochloride or the dihydrochloride monohydrate; alizapride andpharmaceutically acceptable salts and solvates thereof, especially itshydrochloride; clebopride and pharmaceutically acceptable salts andsolvates thereof, especially its malate and the hydrochloridemonohydrate; meclizine (meclozine) and pharmaceutically acceptable saltsand solvates thereof, especially its hydrochloride monohydrate;promethazine and pharmaceutically acceptable salts and solvates thereof,especially its hydrochloride; chlorpromazine and pharmaceuticallyacceptable salts and solvates thereof, especially its hydrochloride;prochlorperazine and pharmaceutically acceptable salts and solvatesthereof, especially its dimaleate, its dimesylate and its the1,2-ethanedisulfonate (1:1) (edisilate); hydroxyzine andpharmaceutically acceptable salts and solvates thereof such as thedihydrochloride or the 1,1′-methylenebis(2-hydroxy-3-naphthalenecarboxylic acid (pamoate); dronabinol;nabilone; aprepitant; netupitant, rolapitant; and casopitant.

In the combination of the present invention, the non-anticholinergicantiemetic agent, Component (b) is present in an amount of from 50% to600%, normally 50% to 300%, of the amount of the saidnon-anticholinergic antiemetic agent contained as a sole activeingredient in the currently used brand or generic drugs. Each of saidtypical non-anticholinergic antiemetic agents is present, in admixturewith a pharmaceutical carrier or vehicle, in a pharmaceuticalcomposition in dosage unit form, as Component (b), in an amount rangingfrom 50% of the minimum amount to 600%, and in some cases beyond 600%,advantageously from 50% to 300%, normally from 100% to 300%, of themaximum amount of said typical non-anticholinergic antiemetic agentcontained in the corresponding, currently used generic or brand drug forits antiemetic indication in IR form. Advantageously, the currently usedbrand or generic drugs containing the maximum amount of said naAEA maybe used as Component (b) of the combination of the present invention.

Advantageous naAEA in said Component (b) is selected from the groupconsisting of alosetron and pharmaceutically acceptable salts andsolvates thereof, in particular the hydrochloride, in an amount (inalosetron) of from 0.25 mg to 6 mg; azasetron and pharmaceuticallyacceptable salts and solvates thereof, in particular the hydrochloride,in an amount (in azasetron) of from 5 mg to 60 mg; dolasetron andpharmaceutically acceptable salts and solvates thereof, in particularthe mesylate, in an amount (in dolasetron) of from 25 mg to 600 mg;granisetron and pharmaceutically acceptable salts and solvates thereof,in particular the hydrochloride, in an amount (in granisetron) of from0.5 mg to 6 mg; ondansetron and pharmaceutically acceptable salts andsolvates thereof, in particular the hydrochloride dihydrate, in anamount (in ondansetron) of from 2 mg to 64 mg; palonosetron andpharmaceutically acceptable salts and solvated thereof, in particularits hydrochloride, in an amount (in palonosetron) of from 0.25 mg to 3mg; ramosetron and pharmaceutically acceptable salts and solvatesthereof, in particular its hydrochloride, in an amount (in ramosetron)of from 0.0125 mg to 0.3 mg; tropisetron and pharmaceutically acceptablesalts and solvates thereof, in particular the hydrochloride, in anamount of from 2.5 mg to 30 mg; domperidone and pharmaceuticallyacceptable salts and solvates thereof, in an amount (in domperidone) offrom 5 mg to 60 mg; haloperidol, in an amount of from 0.5 mg to 60 mg;chlorpromazine and pharmaceutically acceptable salts and solvatesthereof, in particular the hydrochloride, in an amount (inchlorpromazine) of from 12.5 mg to 600 mg; prochlorperazine andpharmaceutically acceptable salts and solvates thereof, in particularthe dimaleate, in an amount (in prochlorperazine) of from 2.5 mg to 30mg; metoclopramide and pharmaceutically acceptable salts and solvatesthereof, in particular the monohydrochloride monohydrate, in an amount(in metoclopramide) of from 5 mg to 60 mg; bromopride andpharmaceutically acceptable salts and solvates, in particular themonohydrochloride and the dihydrochloride monohydrate, in an amount (inbromopride) of from 5 mg to 60 mg; clebopride and pharmaceuticallyacceptable salts and solvates thereof, in particular the hydrogen malateand the hydrochloride monohydrate, in an amount (in clebopride) of from0.25 mg to 3 mg; levosulpiride, in an amount of from 12.5 mg to 600 mg;alizapride and pharmaceutically acceptable salts thereof, in particularthe hydrochloride, in an amount (in alizapride) of from 25 mg to 300 mg;trimethobenzamide and pharmaceutically acceptable salts thereof such asthe monohydrochloride, in an amount (in trimethobenzamide) of from 50 mgto 600 mg; meclizine (also called meclozine) and pharmaceuticallyacceptable salts and solvates thereof, in an amount (in meclizine) offrom 6.25 mg to 300 mg; promethazine and pharmaceutically acceptablesalts and solvates thereof, in particular the hydrochloride, in anamount (in promethazine) of from 12.5 mg to 150 mg; dronabinol in anamount of from 1.25 mg to 60 mg; nabilone, in an amount of from 0.5 mgto 6 mg; aprepitant, in an amount of from 20 mg to 750 mg; netupitant,in an amount of from 150 mg to 1800 mg; rolapitant, in an amount of from30 mg to 360 mg; and casopitant, in an amount of from 25 mg to 300 mg;in a pharmaceutical composition in admixture with a pharmaceuticalcarrier.

According to an embodiment, the non-anticholinergic antiemetic ispresent, in an IR unit form, in an amount ranging from 50% to 200% ofthe maximum amount of said antiemetic agent contained in the currentlyadministered IR dosage unit forms for the treatment of the above-citeddisorders or, in an ER unit form, in an amount ranging from 75% to 300%of the maximum amount of said antiemetic agent contained in thecurrently administered IR dosage unit forms for the treatment of theabove-cited disorders.

For example, according to this embodiment, among the advantageousnon-anticholinergic antiemetic agents used as Component (b), in saidcomposition ondansetron or a pharmaceutically acceptable salt or solvatethereof, in particular its hydrochloride dihydrate, is present in anamount (in ondansetron) of from 4 mg to 16 mg per dosage unit in an IRunit form or in an amount of from 6 mg to 48 mg, preferably from 16 mgto 32 mg, in an ER unit form; alosetron or a pharmaceutically acceptablesalt thereof, in particular its hydrochloride, is present in an amount(in alosetron) of from 0.5 mg to 2 mg per dosage unit in an IR unit formor in an amount of from 0.75 mg to 3 mg, in an ER unit form; azasetronor a pharmaceutically acceptable salt thereof, in particular itshydrochloride, is present in an amount of from 5 mg to 20 mg per dosageunit in an IR unit form or in an amount of from 7.5 mg to 30 mg,preferably from 10 mg to 30 mg, in an ER unit form; ramosetron or apharmaceutically acceptable salts thereof, in particular itshydrochloride, is present in an amount (in ramosetron) of from 0.025 mgto 0.1 mg per dosage unit in an IR unit form or in an amount of from0.0375 mg to 0.3 mg, preferably from 0.05 mg to 0.3 mg, in an ER unitform; tropisetron or a pharmaceutically acceptable salt thereof, inparticular its hydrochloride, is present in an amount (in tropisetron)of from 2.5 mg to 10 mg per dosage unit in an IR unit form or in anamount of from 3.75 mg to 15 mg, preferably from 5 mg to 15 mg, in an ERunit form; granisetron or a pharmaceutically acceptable salt thereof, inparticular its hydrochloride, is present in an amount (in granisetron)of from 1 mg to 4 mg per dosage unit in an IR unit form or in an amountof from 1.5 mg to 6 mg, in an ER unit form; dolasetron, or apharmaceutically acceptable salt thereof, in particular its mesilate, ispresent in an amount (in dolasetron) of from 50 mg to 200 mg per dosageunit in an IR unit form or in an amount of from 75 mg to 300 mg, in anER unit form; palonosetron, or a pharmaceutically acceptable saltthereof, in particular its hydrochloride, is present (a) in an amount(in palonosetron) of from 0.25 mg to 1 mg in an IR dosage unit form orfrom 0.375 mg to 1.5 mg in an ER dosage unit form, or (b) in an amount(in palonosetron) of from 0.25 mg to 12 mg, in a fixed-dose combinationwith netupitant, in an amount of from 200 mg to 600 mg, said fixed-dosecombination being in an IR dosage unit form; rolapitant, in an amount ofform 30 mg to 120 mg, in an IR dosage unit form or in an amount of from45 mg to 180 mg in an ER dosage unit form; domperidone or apharmaceutically acceptable salt thereof, in particular its maleate, ispresent in an amount (in domperidone) of from 5 mg to 20 mg per dosageunit in an IR unit form or in an amount of from 7.5 mg to 30 mg,preferably from 10 mg to 30 mg, in an ER unit form; metoclopramide or apharmaceutically acceptable salt or solvate thereof, in particular itsmonohydrochloride monohydrate, is present in an amount (inmetoclopramide) of from 5 mg to 20 mg per dosage unit in an IR unit formor in an amount of from 7.5 mg to 30 mg, preferably from 10 mg to 30 mg,in an ER unit form; alizapride or a pharmaceutically acceptable saltthereof, in particular its hydrochloride, is present in an amount (inalizapride) of from 25 mg to 100 mg per dosage unit in an IR unit formor in an amount of from 37.5 mg to 300 mg, preferably from 100 mg to 300mg, in an ER unit form; meclizine or a pharmaceutically acceptable saltthereof, in particular its hydrochloride is present in an amount (inmeclizine) of from 25 mg to 100 mg per dosage unit in an IR unit form orin an amount of from 37.5 mg to 150 mg, preferably from 50 mg to 150 mg,in an ER unit form; chlorpromazine or a pharmaceutically acceptable saltthereof, in particular its hydrochloride is present in an amount (inchlorpromazine) of from 50 mg to 200 mg per dosage unit in an IR unitform or in an amount of from 75 mg to 300 mg, preferably from 100 mg to300 mg, in an ER unit form; prochlorperazine or a pharmaceuticallyacceptable salt thereof, in particular its maleate is present in anamount (in prochlorperazine) of from 2.5 mg to 10 mg per dosage unit inan IR unit form or in an amount of from 3.75 mg to 15 mg, preferablyfrom 5 mg to 15 mg, in an ER unit form; dronabinol is present in anamount of from 5 mg to 20 mg per dosage unit in an IR unit form or in anamount of from 7.5 mg to 30 mg, preferably from 10 mg to 30 mg, in an ERunit form; nabilone is present in an amount of from 0.5 mg to 2 mg perdosage unit in an IR unit form or in an amount of from 0.75 mg to 3 mgper dosage unit in an ER unit form; aprepitant is present in an amountof from 62.5 mg to 250 mg per dosage unit in an IR unit form or in anamount of from 93.75 mg to 325 mg, preferably from 125 mg to 325 mg, inan ER unit form; netupitant is present in an amount of from 150 mg to600 mg, in an IR unit form or in an amount of from 225 to 900 mg,preferably from 300 mg to 900 mg, in an ER unit form; rolapitant, in anamount of form 30 mg to 120 mg, in an IR unit form or in an amount offrom 45 mg to 180 mg, preferably from 60 mg to 180 mg, in an ER unitform; and casopitant is present in an amount of from 25 mg to 100 mg perdosage unit in an IR unit form or in an amount of from 37.5 mg to 150,preferably from 50 mg to 150 mg, in an ER unit form, in admixture with apharmaceutical composition in dosage unit form.

Preferred Component (b) is a pharmaceutical composition in dosage unitform comprising a non-anticholinergic antiemetic agent selected from thegroup consisting of ondansetron and pharmaceutically acceptable saltsand solvates thereof, in an amount (in ondansetron) of from 8 mg to 24mg; granisetron and pharmaceutically acceptable salts and solvatesthereof, in an amount (in granisetron) of from 1 mg to 3 mg; domperidoneand pharmaceutically acceptable salts and solvates thereof, in an amount(in domperidone) of from 10 mg to 30 mg; metoclopramide andpharmaceutically acceptable salts and solvates thereof, in an amount (inmetoclopramide) of from 10 mg to 30 mg; dronabinol, in an amount of from10 mg to 30 mg; nabilone, in an amount of from 1 mg to 3 mg; aprepitant,in an amount of from 125 mg to 375 mg; netupitant, in an amount of from300 mg to 900 mg; rolapitant, in an amount of form 60 mg to 180 mg; andcasopitant, in an amount of from 50 mg to 150 mg, in admixture with apharmaceutical carrier.

Ondansetron may also be used as formulated in a patch, for example asdescribed by Farsiya Fathima et al. in Research in J. Pharm. And Tech.4,4(5), May 2011, 806-814: “Formulation and Evaluation of Matrix-TypeTransdermal Delivery Systemof Ondansetron Hydrochloride Using SolventCasting Technique”, or by Cho, J., Van Duong, A., Nguyen, L. T. T. etal. in Journal of Pharmaceutical Investigation (2016).doi:10.1007/s40005-016-0273-9, published online on 18 Aug. 2016: “Designof transdermal matrix patch containing ondansetron”.

The Donepezil Component (c)

According to the present invention, donepezil or a pharmaceuticallyacceptable salts thereof Component (c) is present in the combination inan amount that is equivalent to 10 mg to 92 mg, preferably from 20 mg to92 mg, normally from 10 mg to 70 mg, preferably from 20 mg to 70 mg ofdonepezil hydrochloride and is administered to a patient at a daily dosethat is equivalent to 10 mg to 92 mg, preferably from 20 mg to 92 mg,normally from 10 mg to 70 mg, preferably from 20 mg to 70 mg ofdonepezil hydrochloride. Donepezil hydrochloride may be administered asa brand product, at multiple 5-mg. 10-mg, or 23 mg doses, but, in viewof the high doses to be administered, it will be manufactured in newpharmaceutical compositions comprising the above donepezil amounts, inparticular an amount of from 20 mg to 92 mg donepezil hydrochloride.

Donepezil hydrochloride may be also used as a brand product, by orallyadministering one or more ARICEPT® immediate-release 5 mg-10 mg-tabletsor, where available, 23 mg-tablets. In particular, donepezilhydrochloride may be orally administered, in combination with theabove-illustrated memantine/solifenacin/naAEA combination, at a dailydose of from 10 mg to 92 mg, preferably from 20 mg to 92 mg, normallyfrom 10 mg to 70 mg, preferably from 20 mg to 70 mg.

According to particular necessities, in particular for use in thetitration phase of the therapy, the donepezil effective amount that ispresent in the above combinations, including the fixed-dosecombinations, may be from 10 mg to 50 mg, in particular of 10 mg, 15 mg,20 mg, 25 mg, 30 mg, 35 mg, 40 mg, and 50 mg.

The Solifenacin Component (b) or (d)

Solifenacin and pharmaceutically acceptable salts and compounds thereof,including the quaternary ammonium salts thereof, and their preparationare described in U.S. Pat. No. 6,017,927, the disclosure of which isincorporated herein in its entirety by reference. Methods for thepreparation and for the purification of solifenacin and its salts, inparticular of solifenacin succinate, are described for example in WO2007/076116, WO 2009/139002, WO 2011/003624 and WO 2012/001481, thedisclosures of which are incorporated herein in their entirety byreference, the disclosures of which are incorporated herein forreference in their entirety.

According to the present invention, solifenacin or a pharmaceuticallyacceptable salts thereof Component (d) is present in the combination inan amount that is equivalent to from 10 mg to 30 mg, advantageously from15 mg to 25 mg, preferably 15 mg of solifenacin succinate and isadministered to a patient at a daily dose that is equivalent to from 10mg to 30 mg, advantageously from 15 mg to 25 mg, preferably 15 mg, ofsolifenacin succinate. Solifenacin succinate may be administered as abrand product (VESIcare® 5-mg and 10.mg) in multiple 5-mg or 10-mgdoses.

In particular:

memantine or a pharmaceutically acceptable salt thereof (Component (a))is in a pharmaceutical composition in dosage unit form, in an amountthat is equivalent to from 5 mg to 30 mg of memantine hydrochloride, inadmixture with a pharmaceutical carrier; and

solifenacin or pharmaceutically acceptable salt thereof (Component (b))is in a pharmaceutical composition in dosage unit form, in an amountthat is equivalent to from 10 mg to 30 mg of solifenacin succinate, inadmixture with a pharmaceutical carrier.

The Combinations

As set forth above, by treating a patient suffering from ahypocholinergic disorder, as hereinabove defined, with adonepezil/solifenacin combination, said patient concomitantly alsotaking memantine, the addition of an anticholinergic antiemetic agent tosaid memantine, especially as a memantine/naAEA fixed-dose combination,assures a safe treatment and allows for the increase of the donepezildoses without any appearance of cholinergic effects.

Thus, in a first embodiment, the present invention provides apharmaceutical combination comprising, as Components,

(a) memantine or a pharmaceutically acceptable salt thereof; and(b) a non-anticholinergic antiemetic agent.

In said combination, said memantine or a pharmaceutically acceptablesalt thereof Component (a) preferably is in a pharmaceutical compositionin dosage unit form, in an amount that is equivalent to from 5 mg to 30mg of memantine hydrochloride, in admixture with a pharmaceuticalcarrier; and said naAEA Component (b) also is in a pharmaceuticalcomposition in dosage unit form, in admixture with a pharmaceuticalcarrier.

Any of the non-anticholinergic antiemetic agents illustrated in theabove “The non-anticholinergic Antiemetic Agent Component (b)” sectionmay be used according to the present invention. Normally, the naAEA isselected form the group consisting of (b1) 5HT3-antagonists, (b2)DA-antagonists, (b3) H1-antagonists, (b4) cannabinoids, and (b5)NK1-antagonists

According to a first aspect of this first embodiment, said combinationis a fixed-dose combination essentially consisting of a pharmaceuticalcomposition in dosage unit form comprising

-   (a) memantine or a pharmaceutically acceptable salt thereof, in an    amount that is equivalent to from 5 mg to 30 mg, preferably from 7    mg to 28 mg, of memantine hydrochloride; and-   (b) a naAEA selected from the group consisting of alosetron and    pharmaceutically acceptable salts and solvates thereof, in    particular the hydrochloride, in an amount (in alosetron) of from    0.25 mg to 6 mg; azasetron and pharmaceutically acceptable salts and    solvates thereof, in particular the hydrochloride, in an amount (in    azasetron) of from 5 mg to 60 mg; dolasetron and pharmaceutically    acceptable salts and solvates thereof, in particular the mesylate,    in an amount (in dolasetron) of from 25 mg to 600 mg; granisetron    and pharmaceutically acceptable salts and solvates thereof, in    particular the hydrochloride, in an amount (in granisetron) of from    0.5 mg to 6 mg; ondansetron and pharmaceutically acceptable salts    and solvates thereof, in particular the hydrochloride dihydrate, in    an amount (in ondansetron) of from 2 mg to 64 mg; palonosetron and    pharmaceutically acceptable salts and solvated thereof, in    particular its hydrochloride, in an amount (in palonosetron) of from    0.25 mg to 3 mg; ramosetron and pharmaceutically acceptable salts    and solvates thereof, in particular its hydrochloride, in an amount    (in ramosetron) of from 0.0125 mg to 0.3 mg; tropisetron and    pharmaceutically acceptable salts and solvates thereof, in    particular the hydrochloride, in an amount of from 2.5 mg to 30 mg;    domperidone and pharmaceutically acceptable salts and solvates    thereof, in an amount (in domperidone) of from 5 mg to 60 mg;    haloperidol, in an amount of from 0.5 mg to 60 mg; chlorpromazine    and pharmaceutically acceptable salts and solvates thereof, in    particular the hydrochloride, in an amount (in chlorpromazine) of    from 12.5 mg to 600 mg; prochlorperazine and pharmaceutically    acceptable salts and solvates thereof, in particular the dimaleate,    in an amount (in prochlorperazine) of from 2.5 mg to 30 mg;    metoclopramide and pharmaceutically acceptable salts and solvates    thereof, in particular the monohydrochloride monohydrate, in an    amount (in metoclopramide) of from 5 mg to 60 mg; bromopride and    pharmaceutically acceptable salts and solvates, in particular the    monohydrochloride and the dihydrochloride monohydrate, in an amount    (in bromopride) of from 5 mg to 60 mg; clebopride and    pharmaceutically acceptable salts and solvates thereof, in    particular the hydrogen malate and the hydrochloride monohydrate, in    an amount (in clebopride) of from 0.25 mg to 3 mg; levosulpiride, in    an amount of from 12.5 mg to 600 mg; alizapride and pharmaceutically    acceptable salts thereof, in particular the hydrochloride, in an    amount (in alizapride) of from 25 mg to 300 mg; trimethobenzamide    and pharmaceutically acceptable salts thereof such as the    monohydrochloride, in an amount (in trimethobenzamide) of from 50 mg    to 600 mg; meclizine (also called meclozine) and pharmaceutically    acceptable salts and solvates thereof, in an amount (in meclizine)    of from 6.25 mg to 300 mg; promethazine and pharmaceutically    acceptable salts and solvates thereof, in particular the    hydrochloride, in an amount (in promethazine) of from 12.5 mg to 150    mg; dronabinol in an amount of from 1.25 mg to 60 mg; nabilone, in    an amount of from 0.5 mg to 6 mg; aprepitant, in an amount of from    20 mg to 750 mg; netupitant, in an amount of from 150 mg to 1800 mg;    rolapitant, in an amount of from 30 mg to 360 mg; and casopitant, in    an amount of from 25 mg to 300 mg,    in admixture with a pharmaceutical carrier or vehicle.

An advantageous new memantine/ondansetron fixed-dose combinationessentially consists of

-   (a) memantine or a pharmaceutically acceptable salt thereof, in    amount that is equivalent to from 5 mg to 30 mg of memantine    hydrochloride; and-   (b) a naAEA selected from the group consisting of ondansetron and    pharmaceutically acceptable salts and solvates thereof, in an amount    (in ondansetron) of from 4 mg to 64 mg,    in admixture with a pharmaceutical carrier or vehicle.

A specific new memantine/ondansetron fixed-dose combination according tothis advantageous aspect of this first embodiment of the presentinvention essentially consists of

-   (a) memantine or a pharmaceutically acceptable salt thereof, in    amount that is equivalent to from 5 mg to 10 mg of memantine    hydrochloride; and-   (b) a naAEA selected from the group consisting of ondansetron and    pharmaceutically acceptable salts and solvates thereof, in an amount    (in ondansetron) of from 4 mg to 32 mg,    in admixture with a pharmaceutical carrier or vehicle in an    IR-formulation.

Another specific new memantine/ondansetron fixed-dose combinationaccording to this first embodiment of the present invention essentiallyconsists of

-   (a) memantine or a pharmaceutically acceptable salt thereof, in    amount that is equivalent to from 7 mg to 28 mg of memantine    hydrochloride; and-   (b) a naAEA selected from the group consisting of ondansetron and    pharmaceutically acceptable salts and solvates thereof, in    particular the hydrochloride dihydrate, in an amount (in    ondansetron) of from 16 mg to 64 mg,    in admixture with a pharmaceutical carrier or vehicle in an    ER-formulation.

Components (a/b), (c) and (d) may be concurrently or sequentiallyadministered once per day to said patient suffering from saidhypocholinergic disorder. This treatment may improve the conditions ofsaid patient and allows, in particular, an improvement of the cognitivefunction due to a neuroprotection induced by said treatment.

In a further first embodiment, the present invention provides apharmaceutical combination comprising, as Components,

-   (c) memantine or a pharmaceutically acceptable salt thereof; and-   (d) solifenacin or a pharmaceutically acceptable salt thereof.

According to the present invention, memantine or pharmaceuticallyacceptable salts thereof is present in the combination in an amount offrom 5 mg to 30 mg, preferably from 7 mg to 28 mg, and is administeredto a patient at a daily dose that is equivalent to from 7 mg to 28 mg ofmemantine hydrochloride.

Memantine may also be administered in its brand formulations, as 10-mgIR form (Namenda®), or 7 mg-28 mg ER-forms. (Namenda® RX)

According to this first embodiment of present invention, solifenacin orpharmaceutically acceptable salts thereof is present in the combinationin an amount that is equivalent to from 10 mg to 30 mg, advantageouslyfrom 15 mg to 25 mg, preferably 15 mg, of solifenacin succinate and isadministered to a patient at a daily dose that is equivalent to from 10mg to 30 mg, advantageously from 15 mg to 25 mg, preferably 15 mg ofsolifenacin succinate. Solifenacin succinate may be administered as abrand product (VESIcare® 5-mg and 10.mg) in multiple 5-mg or single ormultiple 10-mg doses.

Donepezil or a pharmaceutically acceptable salt may be present in thecombination in an amount that is equivalent to from 10 mg to 92 mg,preferably from 20 mg to 92 mg, normally from 10 mg to 70 mg, preferablyfrom 20 mg to 70 mg, as illustrated above. Donepezil hydrochloride maybe administered as brand product (Aricept®) in multiple 5 mg-10 mg- and,where available, 23 mg-unit forms.

A memantine/donepezil fixed-dose combination, known as Namzaric®, mayalso be used according to the present invention.

In particular:

memantine or a pharmaceutically acceptable salt thereof [Component (a)]is in a pharmaceutical composition in dosage unit form, in an amountthat is equivalent to from 5 mg to 30 mg, advantageously from 15 mg to25 mg, of memantine hydrochloride, in admixture with a pharmaceuticalcarrier; and

solifenacin or pharmaceutically acceptable salt thereof [(Component (b)]is in a pharmaceutical composition in dosage unit form, in an amountthat is equivalent to from 10 mg to 30 mg, advantageously from 15 mg to25 mg, of solifenacin succinate, in admixture with a pharmaceuticalcarrier.

In the memantine/solifenacin combination of the present invention,solifenacin, as its succinate salt, may be administered in oralimmediate-release form, by using a brand IR-unit form containing 10 mgof solifenacin succinate or multiple doses of its brand 5-mg or 10-mgIR-unit forms.

According to an advantageous aspect of this first embodiment, thememantine/solifenacin combination consists of:

a pharmaceutical composition comprising memantine hydrochloride, in anamount of from 7 mg to 28 mg in admixture with a pharmaceutical carrierin an ER-form, as Component (a); and

a pharmaceutical composition comprising solifenacin succinate, in anamount of from 10 mg to 30 mg, advantageously from 15 mg to 25 mg, inadmixture with a pharmaceutical carrier in an IR-unit form, as Component(b).

According to a preferred aspect of this first embodiment, thememantine/solifenacin combination is a fixed-dose combinationessentially consisting of a pharmaceutical composition comprising

-   (a) memantine or a pharmaceutically acceptable salt thereof, in an    amount that is equivalent to from 5 mg to 30 mg of memantine    hydrochloride; and-   (b) solifenacin or a pharmaceutical acceptable salt thereof, in an    amount is equivalent to from 10 mg to 30 mg, advantageously from 15    mg to 25 mg, of solifenacin succinate,    -   in admixture with a pharmaceutical carrier or vehicle.

All the aforementioned pharmaceutical compositions are preferably indosage unit form wherein each of the active ingredients or both of themare formulated in admixture with a pharmaceutical carrier, andoptimized, as is known in the art, for their pharmaceutical andtherapeutic use.

In a preferred embodiment, the memantine/solifenacin combinationconsists of:

a pharmaceutical composition comprising memantine hydrochloride, in anamount of from 7 mg to 28 mg in admixture with a pharmaceutical carrierin an ER-form, as Component (a); and

a pharmaceutical composition comprising solifenacin succinate, in anamount of from 10 mg to 30 mg, in admixture with a pharmaceuticalcarrier in an IR-unit form, as Component (b).

In particular, the invention provides a pharmaceutical composition indosage unit form, which comprises (a) memantine hydrochloride, in anamount of from 5 mg to 30 mg; and (b) solifenacin succinate, in anamount of from 10 mg to 30 mg, advantageously from 15 mg to 25 mg,preferably 15 mg, in admixture with a pharmaceutical carrier or vehicle.

The pharmaceutical carrier or vehicles are those commonly used for thepreparation of compositions for oral, buccal and parenteral, inparticular transdermal, administration. Appropriate unit forms comprisethe oral forms such as tablets, soft or hard gelatine capsules, powdersor granulates in sachets and suitably measured oral solutions orsuspensions as well as patches for transdermal administration.

In said unit form memantine, preferably memantine hydrochloride, andsolifenacin, especially solifenacin succinate, are mixed, together orseparately, according to known technologies, in admixture with apharmaceutical carriers or vehicles, in pharmaceutical compositions.

Carrier or vehicles for IR tablets include for example starches,cellulose and derivatives thereof; lubricants such as talc, stearic acidor magnesium stearate; diluents such as talc, powdered cellulose,lactose, starches such as maize or corn starch, mannitol, sorbitol;disaggregating agents such as microcrystalline cellulose orcrospovidone; lubricants such as polyethylene glycol or magnesiumstearate; ligands such as methylcellulose, sodiumcarboxymethylcellulose, alginic acid, alginates; sweeteners, such assaccharose, dextrose, mannitol, saccharin; or flavoring agents such asnatural or synthetic oils.

Carriers or vehicles for orally disintegrating tablets include forexample lubricants, aggregating, sweetening, flavoring or disaggregatingagents as well as agents improving the buccal mucosa absorption ofComponent (a) and/or Component (b) such as sorbitol, mannitol, lactoseand cellulose.

Carriers or vehicles for liquid, normally aqueous, suspensions orsolutions include for example antioxidants, such as sodium metabisulfiteor sodium sulfite, thickening agents, such as microcrystallinecellulose, hydroxypropylcellulose, carboxymethylcellulose orpolyvinylpyrrolidone, presevatives such as methyl paraben, ethylparaben, tetra-sodium ethylenediaminotetracetate (sodium edentate),sodium benzoate or an alkaline salt of sorbic acid, as well as flavoringand sweetening agents.

The sweeteners contained in the orally disintegrating tablets and theliquid suspensions or solutions may be natural, optional reduced sugarssuch as sucrose, dextrose, xylitol, mannitol or sorbitol, or syntheticproduct such as sodium saccharine or aspartame.

The flavoring agents are pharmaceutically acceptable flavors and tastesof synthetic and natural oils, the latter extracted from plants, leaves,flowers, fruits and their combinations, such as cinnamon, peppermint,anise and citron leaves, bitter almond, citrus fruits, in particularorange and/or lemon, linden and grapefruit oils. Also chocolate, vanillaor eucalyptus flavor and essences of fruit, in particular apple, pear,peach, strawberry, cherry, apricot, orange, lemon and grapes may beadvantageously used.

Component (a) and Component (b) are advantageously combined in a fixeddose combination for the simultaneous administration of the twoComponents. These fixed-dose combinations are in pharmaceutical unitforms wherein Component (a) and Component (b) are present, together orseparately, in admixture with a pharmaceutical carrier or vehicle. Inthese unit forms, memantine or a pharmaceutically acceptable saltthereof, especially its hydrochloride, and solifenacin or apharmaceutically acceptable salt thereof, especially its succinate, arepresent in an IR- or ER-formulation.

A pharmaceutical unit form comprising (a) memantine hydrochloride, in apharmaceutical composition comprising said memantine hydrochloride in anamount of from 5 mg to 30 mg, in admixture with a pharmaceutical carrierin extended-release formulation; and (b) solifenacin succinate, in apharmaceutical composition comprising said solifenacin succinate in anamount of from 10 mg to 30 mg, advantageously from 15 mg to 25 mg, inadmixture with a pharmaceutical carrier or vehicle in an immediaterelease formulation, is particularly advantageous.

For oral use, Component (a) and Component (b) are in compositions inadmixture with pharmaceutical excipients in known formulations whereinsaid Components are mixed together or separated, for example in twotablets introduced in a capsule, as described in as described in GB1204580, the disclosure of which is incorporated herein for reference,or in a two-compartment capsule or in a multilayer (bilayer) tabletwherein the two components are both in IR form or wherein the memantinepharmaceutically acceptable salt, especially the hydrochloride, is inER-form, and the solifenacin pharmaceutically acceptable salt,especially the succinate thereof, is in IR-form, according to thetechnologies disclosed in U.S. Pat. No. 7,303,761 or 8,802,143, thedisclosures of which are incorporated herein in their entirety forreference.

Component (a) and Component (b) may also be present in form of one oftheir complexes with a cyclodextrin, for example α-cyclodextrin,β-cyclodextrin, γ-cyclodextrin, 2-hydroxypropyl-β-cyclodextrin ormethyl-β-cyclodextrin.

Component (a) and Component (b) may also be formulated in the form ofmicrocapsules, optionally with one or more carriers or vehicles oradditives.

For oral administration, Component (a) and Component (b), together orseparately, are formulated by mixing the active ingredient withconventional pharmaceutical acceptable carriers or vehicles enablingsaid active ingredients to be formulated in tablets, dragees, orallydisintegrating tablets, capsules, liquid solutions or suspensions,syrups and the like.

The composition according to the present invention may be in form of acapsule containing two tablets as described herein above, one of themcomprising Component (a) and the other comprising Component (b).

The composition of memantine/solifenacin may be formulated in tablets inwhich one or both of the two components is in controlled-release form,for example as a dispersion of said component inhydroxypropyl-methyl-cellulose or in a film-coated microgranule.

Advantageously, memantine, preferably memantine hydrochloride in anER-formulation and in an amount of 7 mg to 28 mg, is in the core, andsolifenacin, preferably solifenacin succinate, in IR-formulation and inan amount of from 10 mg to 30 mg, advantageously from 15 mg to 25 mg, isin the outer layer in a bilayer tablet in which, both the core and theouter layer may be coated with a film.

The memantine/solifenacin fixed-dose combination according to thepresent invention may be also formulated in a bi-layer tablet, the firstlayer containing memantine or a pharmaceutically acceptable salt thereofand the second one containing solifenacin or a pharmaceuticallyacceptable salt thereof. A third layer, free of active substances, couldbe inserted between said first and said second layer.

In said fixed dose combination, the retardant material of said firstlayer and the immediate release carrier second layer are two elementsselected in order to allow respectively an extended (or sustained)release delivery of the memantine pharmaceutically acceptable salts,normally the hydrochloride, and to provide the solifenacinpharmaceutically acceptable salt, normally the succinate, in admixturewith a pharmaceutical carrier for immediate release, for exampleaccording to the technologies described in U.S. Pat. No. 7,303,761 or inU.S. Pat. No. 8,802,143, the disclosures of which are incorporatedherein in their entirety.

An advantageous composition according to this first embodiment consistsof

-   -   Layer A, comprising from 7 mg to 28 mg of memantine        hydrochloride Component (a) in admixture with a pharmaceutical        carrier or vehicle in a ER formulation; and    -   Layer B, comprising from 10 mg to 30 mg, advantageously from 15        mg to 25 mg, preferably 15 mg, of solifenacin succinate        Component (b), in admixture with a pharmaceutical carrier or        vehicle in an IR-formulation,        said composition being destined to be administered once per day,        in combination with a pharmaceutical composition comprising from        10 mg to 92 mg, advantageously from 20 mg to 92 mg, normally        from 10 mg to 70 mg, preferably from 20 mg to 70 mg of donepezil        hydrochloride, also destined to be administered once per day.

Carriers or vehicles and vehicles for ER tablets include retardantmaterials such as is acrylic and methacrylic acid polymers andcopolymers; cellulose derivatives such as hydroxypropylmethylcellulose,hydroxyethylcellulose, hydroxypropylethylcellulose,hydroxypropylcelluloses, methylcellulose, ethylcellulose, or sodiumcarboxymethylcellulose; gums; waxes; glycerides or aliphatic alcohols ora mixture thereof. Thus, a second aspect of this first embodiment of thepresent invention provides the above-illustrated memantine/naAEAcombinations for use for the treatment of a patient suffering from ahypocholinergic disorder in combination with

-   (c) donepezil or a pharmaceutically acceptable salt thereof, at a    daily dose that is equivalent to from 10 mg to 92 mg, preferably    from 20 mg to 92 mg, normally from 10 mg to 70 mg, preferably from    20 mg to 70 mg mg of donepezil hydrochloride; and-   (d) solifenacin or a pharmaceutically acceptable salt thereof, at a    daily dose, that is equivalent to from 10 mg to 30 mg, normally from    15 mg to 25 mg, preferably of 15 mg of solifenacin succinate.

For the intended use, donepezil or pharmaceutically acceptable saltComponent (c) is formulated in a pharmaceutical composition comprisingsaid Component (c) in an amount that is equivalent to from 10 mg to 92mg, preferably from 20 mg to 92 mg, normally from 10 mg to 70 mg,preferably from 20 mg to 70 mg, of donepezil hydrochloride, in admixturewith a pharmaceutical carrier of vehicle preferably in a IR formulation

The pharmaceutical composition comprising Component (c) consisting ofdonepezil hydrochloride may be a generic or brand (for example Aricept®)formulation to be used in single or multiple 5-mg, 10-mg or, whereavailable, 23-mg unit forms.

For the intended use, solifenacin or pharmaceutically acceptable saltComponent (d) is formulated in a pharmaceutical composition comprisingsaid Component (d) in an amount that is equivalent to from 10 mg to 30mg of solifenacin succinate, in admixture with a pharmaceutical carrierof vehicle in a IR formulation.

The pharmaceutical composition comprising Component (d) consisting ofsolifenacin succinate may be a generic or brand (for example VESIcare®)formulation to be used in multiple 5-mg or single or multiple 10-mg unitforms. According to a third aspect of this first embodiment, the presentinvention provides a method for the treatment of a hypocholinergicdisorder, which comprises treating a patient in need of said treatmentwith a combination comprising an effective amount of aN-methyl-D-aspartate receptor antagonist Component (a) selected from thegroup consisting of memantine and pharmaceutical acceptable saltsthereof and an effective amount of a naAEA Component (b), in furthercombination with

-   (c) donepezil or a pharmaceutically acceptable salt thereof, in an    amount that is equivalent to from 10 mg to 92 mg of donepezil    hydrochloride and;-   (d) solifenacin or a pharmaceutically acceptable salt thereof, in an    amount that is equivalent to from 10 mg to 30 mg of solifenacin    succinate.

Said memantine or a pharmaceutically acceptable salt thereof Component(a), is administered at a daily dose that is equivalent to from 5 mg to30 mg more particularly in an IR-formulation, at a daily dose that isequivalent to 20 mg of memantine hydrochloride or an ER-formulation, ata daily dose that is equivalent to from 7 mg to 28 mg of memantinehydrochloride.

Said memantine or a pharmaceutically acceptable salt thereof Component(a) is formulated in a pharmaceutical composition comprising saidmemantine or pharmaceutically acceptable salt thereof in an amount thatis equivalent to from 5 mg to 30 mg, preferably from 7 mg to 28 mg ofmemantine hydrochloride, in admixture with a pharmaceutical carrier orvehicle. Said pharmaceutical composition comprising memantinehydrochloride may be the brand products known as Namenda® and Namenda®XR.

Said naAEA Component (b) is formulated in a pharmaceutical compositionin dosage unit form comprising a naAEA selected from the groupconsisting of alosetron and pharmaceutically acceptable salts andsolvates thereof, in particular the hydrochloride, in an amount (inalosetron) of from 0.25 mg to 6 mg; azasetron and pharmaceuticallyacceptable salts and solvates thereof, in particular the hydrochloride,in an amount (in azasetron) of from 5 mg to 60 mg; dolasetron andpharmaceutically acceptable salts and solvates thereof, in particularthe mesylate, in an amount (in dolasetron) of from 25 mg to 600 mg;granisetron and pharmaceutically acceptable salts and solvates thereof,in particular the hydrochloride, in an amount (in granisetron) of from0.5 mg to 6 mg; ondansetron and pharmaceutically acceptable salts andsolvates thereof, in particular the hydrochloride dihydrate, in anamount (in ondansetron) of from 2 mg to 64 mg; palonosetron andpharmaceutically acceptable salts and solvated thereof, in particularits hydrochloride, in an amount (in palonosetron) of from 0.25 mg to 3mg; ramosetron and pharmaceutically acceptable salts and solvatesthereof, in particular its hydrochloride, in an amount (in ramosetron)of from 0.0125 mg to 0.3 mg; tropisetron and pharmaceutically acceptablesalts and solvates thereof, in particular the hydrochloride, in anamount of from 2.5 mg to 30 mg; domperidone and pharmaceuticallyacceptable salts and solvates thereof, in an amount (in domperidone) offrom 5 mg to 60 mg; haloperidol, in an amount of from 0.5 mg to 60 mg;chlorpromazine and pharmaceutically acceptable salts and solvatesthereof, in particular the hydrochloride, in an amount (inchlorpromazine) of from 12.5 mg to 600 mg; prochlorperazine andpharmaceutically acceptable salts and solvates thereof, in particularthe dimaleate, in an amount (in prochlorperazine) of from 2.5 mg to 30mg; metoclopramide and pharmaceutically acceptable salts and solvatesthereof, in particular the monohydrochloride monohydrate, in an amount(in metoclopramide) of from 5 mg to 60 mg; bromopride andpharmaceutically acceptable salts and solvates, in particular themonohydrochloride and the dihydrochloride monohydrate, in an amount (inbromopride) of from 5 mg to 60 mg; clebopride and pharmaceuticallyacceptable salts and solvates thereof, in particular the hydrogen malateand the hydrochloride monohydrate, in an amount (in clebopride) of from0.25 mg to 3 mg; levosulpiride, in an amount of from 12.5 mg to 600 mg;alizapride and pharmaceutically acceptable salts thereof, in particularthe hydrochloride, in an amount (in alizapride) of from 25 mg to 300 mg;trimethobenzamide and pharmaceutically acceptable salts thereof such asthe monohydrochloride, in an amount (in trimethobenzamide) of from 50 mgto 600 mg; meclizine (also called meclozine) and pharmaceuticallyacceptable salts and solvates thereof, in an amount (in meclizine) offrom 6.25 mg to 300 mg; promethazine and pharmaceutically acceptablesalts and solvates thereof, in particular the hydrochloride, in anamount (in promethazine) of from 12.5 mg to 150 mg; dronabinol in anamount of from 1.25 mg to 60 mg; nabilone, in an amount of from 0.5 mgto 6 mg; aprepitant, in an amount of from 20 mg to 750 mg; netupitant,in an amount of from 150 mg to 1800 mg; rolapitant, in an amount of from30 mg to 360 mg; and casopitant, in an amount of from 25 mg to 300 mg,in admixture with a pharmaceutical carrier or vehicle.

Preferably, in said pharmaceutical composition, said naAEA is selectedfrom the group consisting of alosetron hydrochloride, in an amount (inalosetron) of from 0.25 mg to 6 mg; azasetron hydrochloride, in anamount (in azasetron) of from 5 mg to 60 mg; dolasetron mesylate, in anamount (in dolasetron) of from 25 mg to 600 mg; granisetronhydrochloride, in an amount (in granisetron) of from 0.5 mg to 6 mg;ondansetron hydrochloride dihydrate, in an amount (in ondansetron) offrom 2 mg to 64 mg; hydrochloride, in an amount (in palonosetron) offrom 0.25 mg to 3 mg; ramosetron hydrochloride, in an amount (inramosetron) of from 0.0125 mg to 0.3 mg; tropisetron hydrochloride, inan amount of from 2.5 mg to 30 mg; domperidone, in an amount (indomperidone) of from 5 mg to 60 mg; haloperidol, in an amount of from0.5 mg to 60 mg; chlorpromazine hydrochloride, in an amount (inchlorpromazine) of from 12.5 mg to 600 mg; prochlorperazine dimaleate,in an amount (in prochlorperazine) of from 2.5 mg to 30 mg;metoclopramide monohydrochloride monohydrate, in an amount (inmetoclopramide) of from 5 mg to 60 mg; bromopride monohydrochloride ordihydrochloride monohydrate, in an amount (in bromopride) of from 5 mgto 60 mg; clebopride hydrogen malate or hydrochloride monohydrate, in anamount (in clebopride) of from 0.25 mg to 3 mg; levosulpiride, in anamount of from 12.5 mg to 600 mg; alizapride hydrochloride, in an amount(in alizapride) of from 25 mg to 300 mg; trimethobenzamidemonohydrochloride, in an amount (in trimethobenzamide) of from 50 mg to600 mg; meclizine, in an amount of from 6.25 mg to 300 mg; promethazinehydrochloride, in an amount (in promethazine) of from 12.5 mg to 150 mg;dronabinol in an amount of from 1.25 mg to 60 mg; nabilone, in an amountof from 0.5 mg to 6 mg; aprepitant, in an amount of from 20 mg to 750mg; netupitant, in an amount of from 150 mg to 1800 mg; rolapitant, inan amount of from 30 mg to 360 mg; and casopitant, in an amount of from25 mg to 300 mg, in admixture with a pharmaceutical carrier or vehicle.Any of these naAEAs preferably is in a generic or brand product,preferably in the maximum amount contained in said generic or brandproduct.

Another advantageous pharmaceutical composition comprising a naAEAComponent (b) may be the brand product consisting of a pharmaceuticalcomposition comprising palonosetron hydrochloride, in an amount, inpalonosetron, of 0.5 mg and netupitant, in an amount of 300 mg, inadmixture with a pharmaceutical carrier, known under as Akynzeo®.

In the present method, the donepezil or pharmaceutically acceptable saltComponent (c) is formulated in a pharmaceutical composition comprisingsaid Component (c) in an amount that is equivalent to from 10 mg to 92mg, preferably from 20 mg to 92 mg, normally from 10 mg to 70 mg,preferably from 20 mg to 70 mg, of donepezil hydrochloride, in admixturewith a pharmaceutical carrier of vehicle preferably in a IR formulation

The pharmaceutical composition comprising Component (c) consisting ofdonepezil hydrochloride may be a generic or brand (for example Aricept®)formulation to be used in single or multiple 5-mg, 10-mg or, whereavailable, 23-mg unit forms.

In the present method, the solifenacin or pharmaceutically acceptablesalt Component (d) is formulated in a pharmaceutical compositioncomprising said Component (d) in an amount that is equivalent to from 10mg to 30 mg of solifenacin succinate, in admixture with a pharmaceuticalcarrier of vehicle in a IR formulation.

The pharmaceutical composition comprising Component (d) consisting ofsolifenacin succinate may be a generic or brand (for example VESIcare®)formulation to be used in multiple 5-mg or single or multiple 10-mg unitforms.

According to a fourth aspect of this first embodiment, the inventionprovides a method for the treatment of a hypocholinergic disorder, whichcomprises treating a patient in need of said treatment with a fixed-dosecombination essentially consisting of

-   (a/b) a pharmaceutical composition in dosage unit form comprising    -   (a) memantine or pharmaceutically acceptable salt thereof in an        amount that is equivalent to from 5 mg to 30 mg, preferably from        7 mg to 28 mg of memantine hydrochloride; and    -   (b) a naAEA selected from the group consisting of alosetron and        pharmaceutically acceptable salts and solvates thereof, in        particular the hydrochloride, in an amount (in alosetron) of        from 0.25 mg to 6 mg; azasetron and pharmaceutically acceptable        salts and solvates thereof, in particular the hydrochloride, in        an amount (in azasetron) of from 5 mg to 60 mg; dolasetron and        pharmaceutically acceptable salts and solvates thereof, in        particular the mesylate, in an amount (in dolasetron) of from 25        mg to 600 mg; granisetron and pharmaceutically acceptable salts        and solvates thereof, in particular the hydrochloride, in an        amount (in granisetron) of from 0.5 mg to 6 mg; ondansetron and        pharmaceutically acceptable salts and solvates thereof, in        particular the hydrochloride dihydrate, in an amount (in        ondansetron) of from 2 mg to 64 mg; palonosetron and        pharmaceutically acceptable salts and solvated thereof, in        particular its hydrochloride, in an amount (in palonosetron) of        from 0.25 mg to 3 mg; ramosetron and pharmaceutically acceptable        salts and solvates thereof, in particular its hydrochloride, in        an amount (in ramosetron) of from 0.0125 mg to 0.3 mg;        tropisetron and pharmaceutically acceptable salts and solvates        thereof, in particular the hydrochloride, in an amount of from        2.5 mg to 30 mg; domperidone and pharmaceutically acceptable        salts and solvates thereof, in an amount (in domperidone) of        from 5 mg to 60 mg; haloperidol, in an amount of from 0.5 mg to        60 mg; chlorpromazine and pharmaceutically acceptable salts and        solvates thereof, in particular the hydrochloride, in an amount        (in chlorpromazine) of from 12.5 mg to 600 mg; prochlorperazine        and pharmaceutically acceptable salts and solvates thereof, in        particular the dimaleate, in an amount (in prochlorperazine) of        from 2.5 mg to 30 mg; metoclopramide and pharmaceutically        acceptable salts and solvates thereof, in particular the        monohydrochloride monohydrate, in an amount (in metoclopramide)        of from 5 mg to 60 mg; bromopride and pharmaceutically        acceptable salts and solvates, in particular the        monohydrochloride and the dihydrochloride monohydrate, in an        amount (in bromopride) of from 5 mg to 60 mg; clebopride and        pharmaceutically acceptable salts and solvates thereof, in        particular the hydrogen malate and the hydrochloride        monohydrate, in an amount (in clebopride) of from 0.25 mg to 3        mg; levosulpiride, in an amount of from 12.5 mg to 600 mg;        alizapride and pharmaceutically acceptable salts thereof, in        particular the hydrochloride, in an amount (in alizapride) of        from 25 mg to 300 mg; trimethobenzamide and pharmaceutically        acceptable salts thereof such as the monohydrochloride, in an        amount (in trimethobenzamide) of from 50 mg to 600 mg; meclizine        (also called meclozine) and pharmaceutically acceptable salts        and solvates thereof, in an amount (in meclizine) of from 6.25        mg to 300 mg; promethazine and pharmaceutically acceptable salts        and solvates thereof, in particular the hydrochloride, in an        amount (in promethazine) of from 12.5 mg to 150 mg; dronabinol        in an amount of from 1.25 mg to 60 mg; nabilone, in an amount of        from 0.5 mg to 6 mg; aprepitant, in an amount of from 20 mg to        750 mg; netupitant, in an amount of from 150 mg to 1800 mg;        rolapitant, in an amount of from 30 mg to 360 mg; and        casopitant, in admixture with a pharmaceutical carrier or        vehicle;    -   (c) a pharmaceutical composition in dosage unit form comprising        donepezil or a pharmaceutically acceptable salt thereof, in an        amount that is equivalent to from 10 mg to 92 mg of donepezil        hydrochloride, in admixture with a pharmaceutical carrier or        vehicle and;    -   (d) a pharmaceutical composition in dosage unit form comprising        solifenacin or a pharmaceutically acceptable salt thereof, in an        amount that is equivalent to from 10 mg to 30 mg of solifenacin        succinate, in admixture with a pharmaceutical carrier or        vehicle.

Said Component (c) is donepezil or a pharmaceutically acceptable saltthereof, in a pharmaceutical composition comprising said donepezil orpharmaceutically acceptable salt thereof in an amount that is equivalentto from 10 mg to 92 mg, preferably from 20 mg to 92 mg, normally from 10mg to 70 mg, preferably from 20 mg to 70 mg of donepezil hydrochloride.Donepezil hydrochloride Component (c) may be also used as a brandproduct, by orally administering one or more ARICEPT® immediate-release5 mg-10 mg-tablets or, where available, 23 mg-tablets.

Said Component (d) is solifenacin or a pharmaceutically acceptable saltthereof, in a pharmaceutical composition comprising said solifenacin orpharmaceutically acceptable salt thereof in an amount that is equivalentto from 10 mg to 30 mg, advantageously from 15 mg to 25 mg, preferablyof 15 mg, of solifenacin succinate. Solifenacin succinate Component (d)may be administered as a brand product (VESIcare® 5-mg and 10.mg) inmultiple 5-mg or 10-mg doses.

According to a preferred, fifth aspect of this first embodiment, theinvention provides the combination of the above second aspect of thisfirst embodiment, wherein donepezil Component (c) andsolifenacin/Component (d) are formulated in a fixed-dose combination, asillustrated above, essentially consisting of a pharmaceuticalcomposition in dosage unit form comprising

-   (c) donepezil or a pharmaceutically acceptable salt thereof, in an    amount that is equivalent to from 10 mg to 92 mg of donepezil    hydrochloride; and-   (d) solifenacin or a pharmaceutically acceptable salt thereof, in an    amount that is equivalent to from 10 mg to 30 mg of solifenacin    succinate,    in admixture with a pharmaceutical carrier or vehicle, preferably in    an IR-formulation.

Specifically this fifth aspect of this first embodiment, the presentinvention provides a pharmaceutical combination essentially consistingof

-   (a/b) a pharmaceutical composition in dosage unit form comprising    -   (a) memantine hydrochloride, in an amount of from 5 mg to 30 mg,        preferably from 7 mg to 28 mg; and    -   (b) a naAEA selected from the group consisting of alosetron and        pharmaceutically acceptable salts and solvates thereof, in        particular the hydrochloride, in an amount (in alosetron) of        from 0.25 mg to 6 mg; azasetron and pharmaceutically acceptable        salts and solvates thereof, in particular the hydrochloride, in        an amount (in azasetron) of from 5 mg to 60 mg; dolasetron and        pharmaceutically acceptable salts and solvates thereof, in        particular the mesylate, in an amount (in dolasetron) of from 25        mg to 600 mg; granisetron and pharmaceutically acceptable salts        and solvates thereof, in particular the hydrochloride, in an        amount (in granisetron) of from 0.5 mg to 6 mg; ondansetron and        pharmaceutically acceptable salts and solvates thereof, in        particular the hydrochloride dihydrate, in an amount (in        ondansetron) of from 2 mg to 64 mg; palonosetron and        pharmaceutically acceptable salts and solvated thereof, in        particular its hydrochloride, in an amount (in palonosetron) of        from 0.25 mg to 3 mg; ramosetron and pharmaceutically acceptable        salts and solvates thereof, in particular its hydrochloride, in        an amount (in ramosetron) of from 0.0125 mg to 0.3 mg;        tropisetron and pharmaceutically acceptable salts and solvates        thereof, in particular the hydrochloride, in an amount of from        2.5 mg to 30 mg; domperidone and pharmaceutically acceptable        salts and solvates thereof, in an amount (in domperidone) of        from 5 mg to 60 mg; haloperidol, in an amount of from 0.5 mg to        60 mg; chlorpromazine and pharmaceutically acceptable salts and        solvates thereof, in particular the hydrochloride, in an amount        (in chlorpromazine) of from 12.5 mg to 600 mg; prochlorperazine        and pharmaceutically acceptable salts and solvates thereof, in        particular the dimaleate, in an amount (in prochlorperazine) of        from 2.5 mg to 30 mg; metoclopramide and pharmaceutically        acceptable salts and solvates thereof, in particular the        monohydrochloride monohydrate, in an amount (in metoclopramide)        of from 5 mg to 60 mg; bromopride and pharmaceutically        acceptable salts and solvates, in particular the        monohydrochloride and the dihydrochloride monohydrate, in an        amount (in bromopride) of from 5 mg to 60 mg; clebopride and        pharmaceutically acceptable salts and solvates thereof, in        particular the hydrogen malate and the hydrochloride        monohydrate, in an amount (in clebopride) of from 0.25 mg to 3        mg; levosulpiride, in an amount of from 12.5 mg to 600 mg;        alizapride and pharmaceutically acceptable salts thereof, in        particular the hydrochloride, in an amount (in alizapride) of        from 25 mg to 300 mg; trimethobenzamide and pharmaceutically        acceptable salts thereof such as the monohydrochloride, in an        amount (in trimethobenzamide) of from 50 mg to 600 mg; meclizine        (also called meclozine) and pharmaceutically acceptable salts        and solvates thereof, in an amount (in meclizine) of from 6.25        mg to 300 mg; promethazine and pharmaceutically acceptable salts        and solvates thereof, in particular the hydrochloride, in an        amount (in promethazine) of from 12.5 mg to 150 mg; dronabinol        in an amount of from 1.25 mg to 60 mg; nabilone, in an amount of        from 0.5 mg to 6 mg; aprepitant, in an amount of from 20 mg to        750 mg; netupitant, in an amount of from 150 mg to 1800 mg;        rolapitant, in an amount of from 30 mg to 360 mg; and        casopitant, in admixture with a pharmaceutical carrier or        vehicle; and-   (c/d) a pharmaceutical composition in dosage unit form comprising    -   (c) donepezil hydrochloride, in an amount of from 10 mg to 92        mg, preferably from 20 mg to 92 mg, normally from 10 mg to 70        mg, preferably from 20 mg to 70 mg; and    -   (d) solifenacin succinate, in an amount of from 10 mg to 30,        advantageously from 15 mg to 25 mg, preferably of 15 mg,    -   in admixture with a pharmaceutical carrier or vehicle.

As set forth above, in the case of particular necessities, especiallyfor use in the titration phase of the therapy, the donepezilhydrochloride effective amount that is present in the above fixed-dosecombinations Component (c/d), may be from 10 mg to 50 mg, in particularof 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg.

According to a second embodiment, the present invention provides thecombination of a NMDA-antagonist Component (a) selected from the groupconsisting of memantine and pharmaceutically acceptable salts thereof,any naAEA Component (b) as illustrated herein above in the “The naAEAComponent (b)” section; a ChEI Component (c) selected from the groupconsisting of donepezil and pharmaceutically acceptable salts thereof,and a nsPAChA Component (d) selected from the group consisting ofsolifenacin and pharmaceutically acceptable salts thereof, eachformulated in pharmaceutical composition in admixture with apharmaceutical carrier.

In particular, the combination of the present invention may be acombination comprising or consisting essentially of

-   (a) memantine or a pharmaceutically acceptable salts and solvates    thereof, in a pharmaceutical composition in admixture with a    pharmaceutical carrier or vehicle;-   (b) any naAEA described herein above, each in a pharmaceutical    composition in admixture with a pharmaceutical carrier or vehicle,    said naAEA being preferably selected from the group consisting of    alosetron and pharmaceutically acceptable salts and solvates    thereof; dolasetron and pharmaceutically acceptable salts and    solvates thereof; granisetron and pharmaceutically acceptable salts    and solvates thereof; ondansetron and pharmaceutically acceptable    salts and solvates thereof; palonosetron and pharmaceutically    acceptable salts and solvates thereof; domperidone and    pharmaceutically acceptable salts and solvates thereof; tropisetron    and pharmaceutically acceptable salts and solvates thereof;    domperidone and pharmaceutically acceptable salts and solvates    thereof; haloperidol; chlorpromazine and pharmaceutically acceptable    salts and solvates thereof; prochlorperazine and pharmaceutically    acceptable salts and solvates thereof; metoclopramide and    pharmaceutically acceptable salts and solvates thereof; bromopride    and pharmaceutically acceptable salts and solvates thereof;    clebopride and pharmaceutically acceptable salts and solvates    thereof; levosulpiride; alizapride and pharmaceutically acceptable    salts thereof; trimethobenzamide and pharmaceutically acceptable    salts thereof; meclizine (also called meclozine) and    pharmaceutically acceptable salts and solvates thereof; promethazine    and pharmaceutically acceptable salts and solvates thereof;    dronabinol; nabilone; aprepitant; netupitant; rolapitant;    casopitant;-   (c) donepezil or a pharmaceutically acceptable salt thereof, in a    pharmaceutical composition in admixture with a pharmaceutical    carrier or vehicle; and-   (d) solifenacin or a pharmaceutically acceptable salt thereof, in a    pharmaceutical composition in admixture with a pharmaceutical    carrier or vehicle.

In the above combination, each of the Components (a), (b), (c) and (d)are in pharmaceutical composition in dosage unit form wherein each ofsaid components is in admixture with a pharmaceutical carrier in IR- orER formulation.

In particular the present invention provides, according to a secondembodiment, a pharmaceutical combination comprising or consistingessentially of, as Components:

-   (a) a NMDA-antagonist selected from the group consisting of    memantine and pharmaceutically acceptable salts thereof, in a    pharmaceutical composition in admixture with a pharmaceutical    carrier or vehicle;-   (b) a naAEA selected from the group consisting of (b1)    5HT3-antagonists, (b2) DA-antagonists, (b3) H1-antagonists, (b4)    cannabinoids, (b5) NK1-antagonists, and the netupitant-palonosetron    fixed-dose combination, in a pharmaceutical composition in admixture    with a pharmaceutical carrier or vehicle;-   (c) a ChEI selected from the group consisting of donepezil and    pharmaceutically acceptable salts thereof, in a pharmaceutical    composition in admixture with a pharmaceutical carrier or vehicle;    and-   (d) a nsPAChA selected from the group consisting of solifenacin and    pharmaceutically acceptable salts thereof, in a pharmaceutical    composition in admixture with a pharmaceutical carrier or vehicle.

A first advantageous aspect of this second embodiment provides apharmaceutical combination comprising or consisting essentially of, asComponents:

-   (a) a NMDA-antagonist selected from the group consisting of    memantine and pharmaceutically acceptable salts thereof, in a    pharmaceutical composition in admixture with a pharmaceutical    carrier or vehicle;-   (b). a naAEA consisting of a 5HT3-antagonist selected from the group    consisting of alosetron and pharmaceutically acceptable salts and    solvates thereof, in particular the hydrochloride, in an amount (in    alosetron) of from 0.25 mg to 6 mg; azasetron and pharmaceutically    acceptable salts and solvates thereof, in particular the    hydrochloride, in an amount (in azasetron) of from 5 mg to 60 mg;    dolasetron and pharmaceutically acceptable salts and solvates    thereof, in particular the mesylate, in an amount (in dolasetron) of    from 25 mg to 600 mg; granisetron and pharmaceutically acceptable    salts and solvates thereof, in particular the hydrochloride, in an    amount (in granisetron) of from 0.5 mg to 6 mg; ondansetron and    pharmaceutically acceptable salts and solvates thereof, in    particular the hydrochloride dihydrate, in an amount (in    ondansetron) of from 2 mg to 64 mg; palonosetron and    pharmaceutically acceptable salts thereof, in particular the    hydrochloride, in an amount (in palonosetron) of from 0.25 mg to 3    mg; ramosetron and pharmaceutically acceptable salts thereof, in    particular its hydrochloride, in an amount (in ramosetron) of from    0.0125 mg to 0.3 mg, tropisetron and pharmaceutically acceptable    salts and solvates thereof, in particular the hydrochloride, in an    amount of from 2.5 mg to 30 mg, in a pharmaceutical composition in    admixture with a pharmaceutical carrier or vehicle;-   (c) a ChEI selected from the group consisting of donepezil and    pharmaceutically acceptable salts thereof, in a pharmaceutical    composition in admixture with a pharmaceutical carrier or vehicle;    and-   (d) a nsPAChA selected from the group consisting of solifenacin and    pharmaceutically acceptable salts thereof, in a pharmaceutical    composition in admixture with a pharmaceutical carrier or vehicle.

A second advantageous aspect of this second embodiment provides apharmaceutical combination comprising or consisting essentially of, asComponents:

-   (a) a NMDA-antagonist selected from the group consisting of    memantine and pharmaceutically acceptable salts thereof, in a    pharmaceutical composition in admixture with a pharmaceutical    carrier or vehicle;-   (b) a naAEA consisting of a fixed-dose combination comprising    palonosetron, in an amount of from 0.25 mg to 3 mg of palonosetron    or a pharmaceutically acceptable salt thereof such as its    hydrochloride and from 150 mg to 600 mg of netupitant, in admixture    with a pharmaceutical carrier or vehicle in an oral IR formulation;-   (c) a ChEI selected from the group consisting of donepezil and    pharmaceutically acceptable salts thereof, in a pharmaceutical    composition in admixture with a pharmaceutical carrier or vehicle;    and-   (d) a nsPAChA selected from the group consisting of solifenacin and    pharmaceutically acceptable salts thereof, in a pharmaceutical    composition in admixture with a pharmaceutical carrier or vehicle.

According to this second embodiment, a third advantageous aspect is acombination comprising or consisting essentially of, as Components:

-   (a) a NMDA-antagonist selected from the group consisting of    memantine and pharmaceutically acceptable salts thereof, in a    pharmaceutical composition in admixture with a pharmaceutical    carrier or vehicle;-   (b) a naAEA consisting of a DA-antagonist consisting of domperidone    and pharmaceutically acceptable salts and solvates thereof such as    the maleate; chlorpromazine and pharmaceutically acceptable salts    and solvates thereof such as the hydrochloride; prochlorperazine and    its salts and solvates, particularly the dimaleate and the    dimesylate; promethazine and pharmaceutically acceptable salts and    solvates thereof such as the hydrochloride; and 4-aminosalicylamide    derivatives such as metoclopramide and pharmaceutically acceptable    salts and solvates thereof such as the hydrochloride monohydrate,    bromopride and pharmaceutically acceptable salts and solvates    thereof such as the monohydrochloride or the dihydrochloride    monohydrate, alizapride and pharmaceutically acceptable salts and    solvates thereof such as the hydrochloride, and clebopride and    pharmaceutically acceptable salts and solvates thereof such as the    malate and the hydrochloride monohydrate; in a pharmaceutical    composition in admixture with a pharmaceutical carrier or vehicle a    nsPAChA selected from the group consisting of solifenacin and    pharmaceutically acceptable salts thereof, in a pharmaceutical    composition in admixture with a pharmaceutical carrier or vehicle;-   (c) a ChEI selected from the group consisting of donepezil and    pharmaceutically acceptable salts thereof, in a pharmaceutical    composition in admixture with a pharmaceutical carrier or vehicle;    and-   (d) a nsPAChA selected from the group consisting of solifenacin and    pharmaceutically acceptable salts thereof, in a pharmaceutical    composition in admixture with a pharmaceutical carrier or vehicle.

Preferably, said naAEA Component (b) is a DA-antagonist consisting ofdomperidone or a pharmaceutically acceptable salt thereof, in particularits maleate, in an amount (in domperidone) of from 5 mg to 20 mg perdosage unit in an IR unit form or in an amount of from 7.5 mg to 60 mg,preferably from 10 mg to 60 mg, in an ER unit form; metoclopramide or apharmaceutically acceptable salt or solvate thereof, in particular itsmonohydrochloride monohydrate, in an amount (in metoclopramide) of from5 mg to 20 mg per dosage unit in an IR unit form or in an amount of from7.5 mg to 30 mg, preferably from 10 mg to 30 mg, in an ER unit form;alizapride or a pharmaceutically acceptable salt thereof, in particularits hydrochloride, in an amount (in alizapride) of from 25 mg to 100 mgper dosage unit in an IR unit form or in an amount of from 37.5 mg to300 mg, preferably from 100 mg to 300 mg, in an ER unit form; in apharmaceutical composition in admixture with a pharmaceutical carrier orvehicle.

A fourth advantageous aspect of this second embodiment, is a combinationcomprising or consisting essentially of the following Components

-   (a) a NMDA-antagonist selected from the group consisting of    memantine and pharmaceutically acceptable salts thereof, in a    pharmaceutical composition in admixture with a pharmaceutical    carrier or vehicle;-   (b) a naAEA consisting of a histamine H1 receptor antagonists    selected from the group consisting of meclizine (meclozine) and    pharmaceutically acceptable salts and solvates thereof such as the    hydrochloride monohydrate; promethazine and pharmaceutically    acceptable salts and solvates thereof such as the hydrochloride;    chlorpromazine and pharmaceutically acceptable salts and solvates    thereof such as the hydrochloride, prochlorperazine and    pharmaceutically acceptable salts and solvates thereof such as the    dimaleate, the dimesylate or the 1,2-ethanedisulfonate (1:1)    (edisilate); hydroxyzine and pharmaceutically acceptable salts and    solvates thereof such as the dihydrochloride or the 1,1′-methylene    bis(2-hydroxy-3-naphthalenecarboxylic acid (pamoate) salt; in a    pharmaceutical composition in admixture with a pharmaceutical    carrier or vehicle;-   (c) a ChEI selected from the group consisting of donepezil and    pharmaceutically acceptable salts thereof, in a pharmaceutical    composition in admixture with a pharmaceutical carrier or vehicle;    and-   (d) a nsPAChA selected from the group consisting of solifenacin and    pharmaceutically acceptable salts thereof, in a pharmaceutical    composition in admixture with a pharmaceutical carrier or vehicle.

Preferably, said naAEA Component (b) is a histamine H1 receptorantagonists selected from the group consisting of meclizine or apharmaceutically acceptable salt thereof, in particular itshydrochloride, in an amount (in meclizine) of from 25 mg to 100 mg perdosage unit in an IR unit form or in an amount of from 37.5 mg to 150mg, preferably from 50 mg to 150 mg, in an ER unit form; chlorpromazineor a pharmaceutically acceptable salt thereof, in particular itshydrochloride, in an amount (in chlorpromazine) of from 50 mg to 200 mgper dosage unit in an IR unit form or in an amount of from 75 mg to 300mg, preferably from 100 mg to 300 mg, in an ER unit form;prochlorperazine or a pharmaceutically acceptable salt thereof, inparticular its maleate, in an amount (in prochlorperazine) of from 2.5mg to 10 mg per dosage unit in an IR unit form or in an amount of from3.75 mg to 15 mg, preferably from 5 mg to 15 mg, in an ER unit form; ina pharmaceutical composition in admixture with a pharmaceutical carrieror vehicle.

A fifth advantageous combination according to this second embodiment, isa combination comprising or consisting essentially of the followingComponents

-   (a) a NMDA-antagonist selected from the group consisting of    memantine and pharmaceutically acceptable salts thereof, in a    pharmaceutical composition in admixture with a pharmaceutical    carrier or vehicle;-   (b) a naAEA consisting of a NK1-antagonist selected from the group    consisting of aprepitant, casopitant, netupitant and rolapitant, in    a pharmaceutical composition in admixture with a pharmaceutical    carrier or vehicle;-   (c) a ChEI selected from the group consisting of donepezil and    pharmaceutically acceptable salts thereof, in a pharmaceutical    composition in admixture with a pharmaceutical carrier or vehicle;    and-   (d) a nsPAChA selected from the group consisting of solifenacin and    pharmaceutically acceptable salts thereof, in a pharmaceutical    composition in admixture with a pharmaceutical carrier or vehicle.

A sixth, preferred combination according to this second embodiment is acombination comprising or consisting essentially of the followingComponents:

-   (a) a NMDA-antagonist selected from the group consisting of    memantine and pharmaceutically acceptable salts thereof, in a    pharmaceutical composition in admixture with a pharmaceutical    carrier or vehicle;-   (b) a naAEA selected from the group consisting of alosetron and    pharmaceutically acceptable salts and solvates thereof, in    particular the hydrochloride, in an amount (in alosetron) of from    0.25 mg to 6 mg; azasetron and pharmaceutically acceptable salts and    solvates thereof, in particular the hydrochloride, in an amount (in    azasetron) of from 5 mg to 60 mg; dolasetron and pharmaceutically    acceptable salts and solvates thereof, in particular the mesylate,    in an amount (in dolasetron) of from 25 mg to 600 mg; granisetron    and pharmaceutically acceptable salts and solvates thereof, in    particular the hydrochloride, in an amount (in granisetron) of from    0.5 mg to 6 mg; ondansetron and pharmaceutically acceptable salts    and solvates thereof, in particular the hydrochloride dihydrate, in    an amount (in ondansetron) of from 2 mg to 64 mg; palonosetron and    pharmaceutically acceptable salts and solvated thereof, in    particular its hydrochloride, in an amount (in palonosetron) of from    0.25 mg to 3 mg; ramosetron and pharmaceutically acceptable salts    and solvates thereof, in particular its hydrochloride, in an amount    (in ramosetron) of from 0.0125 mg to 0.3 mg; tropisetron and    pharmaceutically acceptable salts and solvates thereof, in    particular the hydrochloride, in an amount of from 2.5 mg to 30 mg;    domperidone and pharmaceutically acceptable salts and solvates    thereof, in an amount (in domperidone) of from 5 mg to 60 mg;    haloperidol, in an amount of from 0.5 mg to 60 mg; chlorpromazine    and pharmaceutically acceptable salts and solvates thereof, in    particular the hydrochloride, in an amount (in chlorpromazine) of    from 12.5 mg to 600 mg; prochlorperazine and pharmaceutically    acceptable salts and solvates thereof, in particular the dimaleate,    in an amount (in prochlorperazine) of from 2.5 mg to 30 mg;    metoclopramide and pharmaceutically acceptable salts and solvates    thereof, in particular the monohydrochloride monohydrate, in an    amount (in metoclopramide) of from 5 mg to 60 mg; bromopride and    pharmaceutically acceptable salts and solvates, in particular the    monohydrochloride and the dihydrochloride monohydrate, in an amount    (in bromopride) of from 5 mg to 60 mg; clebopride and    pharmaceutically acceptable salts and solvates thereof, in    particular the hydrogen malate and the hydrochloride monohydrate, in    an amount (in clebopride) of from 0.25 mg to 3 mg; levosulpiride, in    an amount of from 12.5 mg to 600 mg; alizapride and pharmaceutically    acceptable salts thereof, in particular the hydrochloride, in an    amount (in alizapride) of from 25 mg to 300 mg; trimethobenzamide    and pharmaceutically acceptable salts thereof such as the    monohydrochloride, in an amount (in trimethobenzamide) of from 50 mg    to 600 mg; meclizine (also called meclozine) and pharmaceutically    acceptable salts and solvates thereof, in an amount (in meclizine)    of from 6.25 mg to 300 mg; promethazine and pharmaceutically    acceptable salts and solvates thereof, in particular the    hydrochloride, in an amount (in promethazine) of from 12.5 mg to 150    mg; dronabinol in an amount of from 1.25 mg to 60 mg; nabilone, in    an amount of from 0.5 mg to 6 mg; aprepitant, in an amount of from    20 mg to 750 mg; netupitant, in an amount of from 150 mg to 1800 mg;    rolapitant, in an amount of from 30 mg to 360 mg; and casopitant; in    a pharmaceutical composition in admixture with a pharmaceutical    carrier or vehicle;-   (c) a ChEI selected from the group consisting of donepezil and    pharmaceutically acceptable salts thereof, in a pharmaceutical    composition in admixture with a pharmaceutical carrier or vehicle;    and-   (d) a nsPAChA selected from the group consisting of solifenacin and    pharmaceutically acceptable salts thereof, in a pharmaceutical    composition in admixture with a pharmaceutical carrier or vehicle

A seventh, particularly advantageous combination according to thissecond embodiment essentially consists of

-   (a) a NMDA-antagonist selected from the group consisting of    memantine or a pharmaceutically acceptable salt thereof, in an    amount of from 5 mg to 30 mg, in admixture with a pharmaceutical    carrier or vehicle;-   (b) a naAEA selected from the group consisting of ondansetron    hydrochloride dihydrate, in an amount (in ondansetron) of from 4 mg    to 64 mg, domperidone, in an amount, in domperidone of from 5 mg to    30 mg; and metoclopramide monohydrochloride monohydrate in an amount    (in metoclopramide) of from 5 mg to 30 mg; in a pharmaceutical    composition in admixture with a pharmaceutical carrier or vehicle;-   (c) a ChEI selected from the group consisting of donepezil and    pharmaceutically acceptable salts thereof, in an amount of from 10    mg to 92 mg, preferably from 20 mg to 92 mg, normally from 10 mg to    70 mg, preferably from 20 mg to 70 mg, in admixture with a    pharmaceutical carrier or vehicle; and-   (d) a nsPAChA selected from the group consisting of solifenacin and    pharmaceutically acceptable salts thereof, in an amount of from 10    mg to 30 mg, advantageously from 15 mg to 25 mg, preferably of 15    mg, in admixture with a pharmaceutical carrier or vehicle.

An eight advantageous combination according to this second embodimentessentially consists of

-   (a) a NMDA-antagonist selected from the group consisting of    memantine or a pharmaceutically acceptable salt thereof, in an    amount of from 5 mg to 30 mg, in admixture with a pharmaceutical    carrier or vehicle;-   (b) a naAEA selected from the group consisting of a    netupitant/palonosetron fixed-dose combination comprising    netupitant, in an amount of 300 mg and palonosetron hydrochloride,    in an amount (in palonosetron) of 0.5, in admixture with a    pharmaceutical carrier or vehicle;-   (c) a ChEI selected from the group consisting of donepezil and    pharmaceutically acceptable salts thereof, in an amount of from 20    mg to 92 mg, in admixture with a pharmaceutical carrier or vehicle;    and-   (d) a nsPAChA selected from the group consisting of solifenacin and    pharmaceutically acceptable salts thereof, in an amount of from 10    mg to 30 mg, advantageously from 15 mg to 25 mg, preferably of 15    mg, in admixture with a pharmaceutical carrier or vehicle.

In the combination according to this eight aspect of this secondembodiment, Component (b) may be used as the palonosetron/netupitantbrand preparation Akynzeo®,

Preferably, according to these six aspects of this first embodiment,memantine Component (a), as hydrochloride, is present in an amount offrom 5 mg to 10 mg in an IR formulation, or in an amount of from 7 mg to28 mg in an ER-formulation. In particular, it may be used as its brandpreparation Namenda®.

According to a further second embodiment, the invention provides theherein above illustrated memantine/solifenacin combination comprising

-   (a) memantine or a pharmaceutically acceptable salt thereof; and-   (b) solifenacin or a pharmaceutically acceptable salt thereof,    -   for use for treating hypocholinergic disorders in further        combination with donepezil or a pharmaceutically acceptable salt        thereof in an amount that is equivalent to from 20 mg to 92 mg        of donepezil hydrochloride, as a single dose.

Thanks to the solifenacin/memantine synergism, said donepezil amount maybe of from 10 mg to 92 mg, advantageously from 20 mg to 92 mg, normallyfrom 10 mg to 70 mg, preferably from 20 mg to 70 mg or from 40 mg to 70mg, as a single dose, with substantially improved therapeutic response.

For the intended use, each of the Components (a) and (b) are formulatedin a pharmaceutical composition. Thus, in the above combination,memantine or a pharmaceutically acceptable salt is in a pharmaceuticalcomposition, preferably in dosage unit form, comprising said memantineor pharmaceutically acceptable salt thereof, in an amount that isequivalent to from 5 mg to 30 mg, preferably from 7 mg to 28 mg, ofmemantine hydrochloride, in admixture with a pharmaceutical carrier orvehicle; and said solifenacin or pharmaceutically acceptable saltthereof is in a pharmaceutical composition, preferably in dosage unitform, comprising said solifenacin or pharmaceutically acceptable saltthereof, in an amount that is equivalent to from 10 mg to 30 mg,advantageously from 15 mg to 25 mg, preferably of 15 mg, of solifenacinsuccinate.

In a further second embodiment, the invention provides a combinationcomprising

-   (a) a pharmaceutical composition comprising memantine or a    pharmaceutically acceptable salt thereof, in an amount that is    equivalent to from 5 mg to 30 mg, preferably from 7 mg to 28 mg, of    memantine hydrochloride, in admixture with a pharmaceutical carrier    or vehicle; and-   (b) a pharmaceutical composition comprising solifenacin or a    pharmaceutically acceptable salt thereof, in an amount that is    equivalent to from 10 mg to 30 mg, advantageously from 15 mg to 25    mg, preferably 15 mg, of solifenacin succinate, in admixture with a    pharmaceutical carrier or vehicle,    for use for treating Alzheimer type dementia in further combination    with a pharmaceutical composition comprising donepezil or a    pharmaceutically acceptable salt thereof.

Said donepezil or pharmaceutically acceptable salt thereof isadministered at a daily dose that is equivalent to from 10 mg to 92 mg,preferably from 20 mg to 92 mg, normally from 10 mg to 70 mg, preferablyfrom 20 mg to 70 mg of donepezil hydrochloride.

Preferably, this memantine/solifenacin combination is a memantinehydrochloride/solifenacin succinate combination for use in combinationwith a pharmaceutical composition comprising donepezil hydrochloride, inan amount of from 10 mg to 92 mg, preferably from 20 mg to 92 mg,normally from 10 mg to 70 mg, preferably from 20 mg to 70 mg, inadmixture with a pharmaceutical carrier or vehicle, administered onceper day.

Thanks to the solifenacin/memantine synergism, said donepezilhydrochloride amount may be of from 10 mg to 92 mg, advantageously from20 mg to 70 mg, or from 40 mg to 70 mg, as a single daily dose, withsubstantially improved therapeutic response.

According to a this preferred embodiment, memantine or apharmaceutically acceptable salt thereof and solifenacin or apharmaceutically acceptable salt thereof are in a fixed-dose combinationas illustrated herein above, Said fixed-dose combination essentiallyconsists of a pharmaceutical composition, preferably in dosage unitform, comprising said memantine or pharmaceutically acceptable saltthereof, in an amount that is equivalent to from 5 mg to 30 mg; and saidsolifenacin or pharmaceutically acceptable salt thereof, in an amountthat is equivalent to from 10 to 30 mg, advantageously from 15 mg to 25mg, preferably of 15 mg, in admixture with a pharmaceutical carrier orvehicle.

The memantine/solifenacin fixed-dose combination according to thispreferred embodiment is useful for an easy and safe treatment ofhypocholinergic disorders in combination with a pharmaceuticalcomposition comprising donepezil or a pharmaceutically acceptable saltthereof, in an amount that is equivalent to from 10 mg to 92 mg,preferably from 20 mg to 92 mg, normally from 10 mg to 70 mg, preferablyfrom 20 mg to 70 mg mg or from 40 mg to 70 mg of donepezilhydrochloride.

Thus, the present invention also provides a method for the treatment ofa hypocholinergic disorder such as Alzheimer type dementia, for examplefrom Alzheimer's dementia, Parkinson's disease, Lewy body diseasedementia and related disorders, which comprises treating a patient inneed of said treatment with an effective amount of aN-methyl-D-aspartate receptor antagonist selected from the groupconsisting of memantine and pharmaceutical acceptable salts thereof[(Component (a)], and with an effective amount of a non-selectiveperipheral anticholinergic agent selected from the group consisting ofsolifenacin and pharmaceutically acceptable salts thereof [Component(b)], in combination with a cholinesterase inhibitor selected from thegroup consisting of donepezil and pharmaceutically acceptable saltsthereof [Component (c)], at a daily dose that is equivalent to from 20mg to 92 mg of donepezil hydrochloride.

According to a particular advantageous aspect of the above method, saidcomponent (a) and said Component (b) are in a fixed-dose combinationessentially consisting of a pharmaceutical composition comprising

(a) memantine or a pharmaceutically acceptable salt thereof, in anamount that is equivalent to from 5 mg to 30 mg, preferably from 7 mg to28 g, of memantine hydrochloride; and

(b) solifenacin or a pharmaceutical acceptable salt thereof, in anamount that is equivalent to from 10 mg to 30 mg, advantageously from 15mg to 25 mg, preferably 15 mg, of solifenacin succinate,

in admixture with a pharmaceutical carrier or vehicle.

This pharmaceutical combinations according to this second embodiment ofthe present invention is useful for the treatment of a hypocholinergicdisorder as herein above defined, and even high doses of a donepezilComponent (c), as illustrated above, may be present to improve symptomswithout adverse effects to a greater extent.

Thus, the present invention provides a method for treating Alzheimertype dementia, which comprises administering to a patient in need ofsaid treatment the combinations described herein above. In such atreatment, Component (a), Component (b), Component (c) and Component (d)of the combination may be administered simultaneously or sequentially tosaid patient, Component (a) being indifferently administered before orafter Component (b), Component (c) and Component (d). Components (a),Component (b), Component (c), and Component (d) may also be administeredby the same or a different administration route.

According to a third embodiment, an advantageousNMDA-antagonist/naAEA/ChEI/nsPAChA combination may be a combinationcomprising or consisting essentially of

-   (a) a NMDA-antagonist selected from the group consisting of    memantine and pharmaceutically acceptable salts thereof, in a    pharmaceutical composition in admixture with a pharmaceutical    carrier or vehicle;-   (b/d) a fixed-dose combination comprising    -   (b) a naAEA; and    -   (d) a nsPAChA selected from the group consisting of solifenacin        and pharmaceutically acceptable salts thereof, in admixture with        a pharmaceutical carrier or vehicle; and-   (c) a ChEI selected from the group consisting of donepezil and    pharmaceutically acceptable salts thereof, in a pharmaceutical    composition in admixture with a pharmaceutical carrier or vehicle.

In the fixed dose combination (b/d), the naAEA may be any one of thosedisclosed in the above “The naAEA Component (b)” section. AdvantageousComponent (b/d) may be a naAEA/solifenacin fixed-dose combinationconsisting of any one of the pharmaceutical compositions described in WO2014/039627 (see also US 2015/0231122), the disclosures of which areincorporated herein in their entirety for reference.

According to an aspect of this third embodiment, the invention providesa combination comprising or consisting essentially of

-   (a) a NMDA-antagonist selected from the group consisting of    memantine and pharmaceutically acceptable salts thereof in an amount    that is equivalent to from 5 mg to 30 mg of memantine hydrochloride,    in a pharmaceutical composition in admixture with a pharmaceutical    carrier or vehicle;-   (b/d) a fixed-dose combination essentially consisting of a    pharmaceutical composition in dosage unit form comprising    -   (b) a naAEA selected from the group consisting of alosetron and        pharmaceutically acceptable salts and solvates thereof, in        particular the hydrochloride, in an amount (in alosetron) of        from 0.25 mg to 6 mg; azasetron and pharmaceutically acceptable        salts and solvates thereof, in particular the hydrochloride, in        an amount (in azasetron) of from 5 mg to 60 mg; dolasetron and        pharmaceutically acceptable salts and solvates thereof, in        particular the mesylate, in an amount (in dolasetron) of from 25        mg to 600 mg; granisetron and pharmaceutically acceptable salts        and solvates thereof, in particular the hydrochloride, in an        amount (in granisetron) of from 0.5 mg to 6 mg; ondansetron and        pharmaceutically acceptable salts and solvates thereof, in        particular the hydrochloride dihydrate, in an amount (in        ondansetron) of from 2 mg to 64 mg; palonosetron and        pharmaceutically acceptable salts and solvated thereof, in        particular its hydrochloride, in an amount (in palonosetron) of        from 0.25 mg to 3 mg; ramosetron and pharmaceutically acceptable        salts and solvates thereof, in particular its hydrochloride, in        an amount (in ramosetron) of from 0.0125 mg to 0.3 mg;        tropisetron and pharmaceutically acceptable salts and solvates        thereof, in particular the hydrochloride, in an amount of from        2.5 mg to 30 mg; domperidone and pharmaceutically acceptable        salts and solvates thereof, in an amount (in domperidone) of        from 5 mg to 60 mg; haloperidol, in an amount of from 0.5 mg to        60 mg; chlorpromazine and pharmaceutically acceptable salts and        solvates thereof, in particular the hydrochloride, in an amount        (in chlorpromazine) of from 12.5 mg to 600 mg; prochlorperazine        and pharmaceutically acceptable salts and solvates thereof, in        particular the dimaleate, in an amount (in prochlorperazine) of        from 2.5 mg to 30 mg; metoclopramide and pharmaceutically        acceptable salts and solvates thereof, in particular the        monohydrochloride monohydrate, in an amount (in metoclopramide)        of from 5 mg to 60 mg; bromopride and pharmaceutically        acceptable salts and solvates, in particular the        monohydrochloride and the dihydrochloride monohydrate, in an        amount (in bromopride) of from 5 mg to 60 mg; clebopride and        pharmaceutically acceptable salts and solvates thereof, in        particular the hydrogen malate and the hydrochloride        monohydrate, in an amount (in clebopride) of from 0.25 mg to 3        mg; levosulpiride, in an amount of from 12.5 mg to 600 mg;        alizapride and pharmaceutically acceptable salts thereof, in        particular the hydrochloride, in an amount (in alizapride) of        from 25 mg to 300 mg; trimethobenzamide and pharmaceutically        acceptable salts thereof such as the monohydrochloride, in an        amount (in trimethobenzamide) of from 50 mg to 600 mg; meclizine        (also called meclozine) and pharmaceutically acceptable salts        and solvates thereof, in an amount (in meclizine) of from 6.25        mg to 300 mg; promethazine and pharmaceutically acceptable salts        and solvates thereof, in particular the hydrochloride, in an        amount (in promethazine) of from 12.5 mg to 150 mg; dronabinol        in an amount of from 1.25 mg to 60 mg; nabilone, in an amount of        from 0.5 mg to 6 mg; aprepitant, in an amount of from 20 mg to        750 mg; netupitant, in an amount of from 150 mg to 1800 mg;        rolapitant, in an amount of from 30 mg to 360 mg; and        casopitant; and-   (d) a nsPAChA selected from the group consisting of solifenacin and    pharmaceutically acceptable salts thereof, in an amount that is    equivalent to from 10 mg to 30 mg, advantageously from 15 mg to 25    mg, preferably of 15 mg of solifenacin succinate, in admixture with    a pharmaceutical carrier or vehicle; and-   (c) a ChEI selected from the group consisting of donepezil and    pharmaceutically acceptable salts thereof, in an amount that is    equivalent to from 20 mg to 92 mg, in a pharmaceutical composition    in admixture with a pharmaceutical carrier or vehicle.

Preferably, the naAEA selected from the group consisting of alosetronhydrochloride, in an amount (in alosetron) of from 0.25 mg to 6 mg;azasetron hydrochloride, in an amount (in azasetron) of from 5 mg to 60mg; dolasetron mesylate, in an amount (in dolasetron) of from 25 mg to600 mg; granisetron hydrochloride, in an amount (in granisetron) of from0.5 mg to 6 mg; ondansetron hydrochloride dihydrate, in an amount (inondansetron) of from 2 mg to 64 mg; palonosetron hydrochloride, in anamount (in palonosetron) of from 0.25 mg to 3 mg; ramosetronhydrochloride, in an amount (in ramosetron) of from 0.0125 mg to 0.3 mg,tropisetron hydrochloride, in an amount (in tropisetron) of from 2.5 mgto 30 mg; domperidone and pharmaceutically acceptable salts and solvatesthereof, in an amount (in domperidone) of from 5 mg to 60 mg;haloperidol, in an amount of from 0.5 mg to 60 mg; chlorpromazinehydrochloride, in an amount (in chlorpromazine) of from 12.5 mg to 600mg; prochlorperazine dimaleate, in an amount (in prochlorperazine) offrom 2.5 mg to 30 mg; metoclopramide monohydrochloride monohydrate, inan amount (in metoclopramide) of from 5 mg to 60 mg; bromopridemonohydrochloride or dihydrochloride monohydrate, in an amount (inbromopride) of from 5 mg to 60 mg; clebopride hydrogen malate orhydrochloride monohydrate, in an amount (in clebopride) of from 0.25 mgto 3 mg; levosulpiride, in an amount of from 12.5 mg to 600 mg;alizapride hydrochloride, in an amount (in alizapride) of from 25 mg to300 mg; trimethobenzamide monohydrochloride, in an amount (intrimethobenzamide) of from 50 mg to 600 mg; meclizine (also calledmeclozine) and pharmaceutically acceptable salts and solvates thereof,in an amount (in meclizine) of from 6.25 mg to 300 mg; promethazinehydrochloride, in an amount (in promethazine) of from 12.5 mg to 150 mg;dronabinol in an amount of from 1.25 mg to 60 mg; nabilone, in an amountof from 0.5 mg to 6 mg; aprepitant, in an amount of from 20 mg to 750mg; netupitant, in an amount of from 150 mg to 1800 mg; rolapitant, inan amount of from 30 mg to 360 mg; and casopitant, in an amount of from25 mg to 300 mg.

In a further third embodiment, the present invention provides amemantine/solifenacin/donepezil combination comprising

-   (a) a pharmaceutical composition in dosage unit form comprising or    consisting essentially of memantine or a pharmaceutically acceptable    salt thereof, preferably its hydrochloride, in admixture with a    pharmaceutical carrier or vehicle in an IR or ER form; and-   (b/c) a fixed-dose combination that is a pharmaceutical composition    comprising or consisting essentially of    -   (b) solifenacin or a pharmaceutically acceptable salt,        preferably its succinate; and    -   (c) donepezil or a pharmaceutically acceptable salt, preferably        its hydrochloride, in admixture with a pharmaceutical carrier or        vehicle, in IR-form.

This combination has the advantage of allowing an improvement in thetreatment of a patient suffering from Alzheimer type dementia. In fact,in the case of the prescription of IR-memantine that must be taken twotimes/day, the Component (b/c) of this third embodiment of the inventionallows the administration of a composition (b/c) comprising solifenacinand donepezil that are administered once a day, thus rendering thetreatment easier for the patient or for the caregiver.

For example, a combination according to this third embodiment maycomprise:

-   (a) a pharmaceutical composition in dosage unit form comprising or    consisting essentially of a memantine pharmaceutically acceptable    salt, preferably the hydrochloride in an amount of from 7 mg to 28    mg in admixture with a pharmaceutical carrier or vehicle in an IR or    ER form, in admixture with a pharmaceutical carrier or vehicle; and-   (b/c) a fixed-dose combination that is a pharmaceutical composition    comprising or consisting essentially of    -   (b) a solifenacin pharmaceutically acceptable salt, preferably        the succinate thereof in an amount of from 10 mg to 30 mg,        advantageously from 15 mg to 25 mg; and    -   (c) a donepezil pharmaceutically acceptable salt, preferably the        hydrochloride thereof in an amount of from 10 mg to 92 mg,        preferably from 20 mg to 92 mg, normally from 10 mg to 70 mg,        preferably from 20 mg to 70 mg;    -   in admixture with a pharmaceutical carrier or vehicle in an IR        form.

An advantageous combination of this third embodiment comprises:

-   (a) a pharmaceutical composition in dosage unit form comprising or    consisting essentially of memantine hydrochloride, in an amount of    from 7 mg to 28 mg in admixture with a pharmaceutical carrier or    vehicle in ER form    in admixture with a pharmaceutical carrier; and-   (b/c) a fixed-dose combination that is a pharmaceutical composition    comprising or consisting essentially of    -   (b) solifenacin succinate, in an amount of 15 mg; and    -   (c) donepezil hydrochloride, in an amount of from 10 mg to 50        mg, normally from 10 mg to 40 mg,    -   in admixture with a pharmaceutical carrier or vehicle, in        IR-form.

As set forth above, this composition is particularly useful in thetitration phase of the treatment of a patient suffering from ahypocholinergic disorder and also during the treatment of saiddisorders, for donepezil doses up to 50 mg single or daily dose.

According to an advantageous aspect of this third embodiment, theinvention provides the above pharmaceutical composition in dosage unitform in a novel formulation wherein the pharmaceutical carrier allowsthat said solifenacin succinate and donepezil hydrochloride do notinteract each other.

In particular, donepezil hydrochloride and solifenacin succinate arepresent in specific percent amount and the pharmaceutical carriercomprises a diluent such as talc, powdered cellulose, lactose; adisaggregating agents such as microcrystalline cellulose, crospovidoneor a starch, for example maize or corn starch; a lubricant such asmagnesium or calcium stearate; and a binder, such as methyl cellulose,ethyl cellulose or hydroxypropyl methyl cellulose, each in specificpercent amounts.

Specifically, the pharmaceutical carrier comprises lactose as a diluent;corn starch as a disaggregating agent; magnesium stearate as alubricant; and hydroxypropyl methyl cellulose as a binder.

Preferably, the pharmaceutical unit form comprising the preferredcomposition according to this third embodiment of the present inventionis a coated tablet containing donepezil hydrochloride, in an amount offrom 10 mg to 50 mg and solifenacin succinate, in an amount of 15 mg, asactive ingredients, in the core, in admixture with a pharmaceuticalcarrier as defined above.

In particular, in the solifenacin/donepezil fixed dose combinationessentially consists in a pharmaceutical composition in a dosage unitform consisting of a coated tablet comprising solifenacin succinate, inan amount of from 5.5% to 6.5%, donepezil hydrochloride, in an amount offrom 4% to 20%; a diluent, in a amount of from 60% to 82%, adisaggregating agent, in a amount of from 6.8% to 7.5%; and a binder, inan amount of from 1.9% to 2.5% the total weight of the core. The coatingis a non-enteric, fast-dissolving layer that covers the core accordingto known technologies. Normally, it is constituted by a cellulosederivative such as methyl hydroxyethyl cellulose or hydroxypropyl methylcellulose, a glycerol ester such as diacetin or triacetin and a pigmentsuch as titanium dioxide. Normally, the coating is Opadry®, especiallythe White 03K18533 type.

A fourth embodiment of the present invention provides a combinationessentially consists of

-   (a/c) a fixed-dose combination consisting of a pharmaceutical    composition in dosage unit form comprising    -   (a) memantine or a pharmaceutically acceptable salt thereof, in        amount that is equivalent to from 5 mg to 30 mg of memantine        hydrochloride; and    -   (c) donepezil or a pharmaceutically acceptable salts thereof, in        an amount that is equivalent to from 10 mg to 92 mg, preferably        from 20 mg to 92 mg, normally from 10 mg to 70 mg, preferably        from 20 mg to 70 mg of donepezil hydrochloride, in a        pharmaceutical composition in admixture with a pharmaceutical        carrier or vehicle;-   (b) a pharmaceutical composition comprising a naAEA selected from    the group consisting of) is selected from the group consisting of    alosetron and pharmaceutically acceptable salts and solvates    thereof, in particular the hydrochloride, in an amount (in    alosetron) of from 0.25 mg to 6 mg; azasetron and pharmaceutically    acceptable salts and solvates thereof, in particular the    hydrochloride, in an amount (in azasetron) of from 5 mg to 60 mg;    dolasetron and pharmaceutically acceptable salts and solvates    thereof, in particular the mesylate, in an amount (in dolasetron) of    from 25 mg to 600 mg; granisetron and pharmaceutically acceptable    salts and solvates thereof, in particular the hydrochloride, in an    amount (in granisetron) of from 0.5 mg to 6 mg; ondansetron and    pharmaceutically acceptable salts and solvates thereof, in    particular the hydrochloride dihydrate, in an amount (in    ondansetron) of from 2 mg to 64 mg; palonosetron and    pharmaceutically acceptable salts and solvated thereof, in    particular its hydrochloride, in an amount (in palonosetron) of from    0.25 mg to 3 mg; ramosetron and pharmaceutically acceptable salts    and solvates thereof, in particular its hydrochloride, in an amount    (in ramosetron) of from 0.0125 mg to 0.3 mg; tropisetron and    pharmaceutically acceptable salts and solvates thereof, in    particular the hydrochloride, in an amount of from 2.5 mg to 30 mg;    domperidone and pharmaceutically acceptable salts and solvates    thereof, in an amount (in domperidone) of from 5 mg to 60 mg;    haloperidol, in an amount of from 0.5 mg to 60 mg; chlorpromazine    and pharmaceutically acceptable salts and solvates thereof, in    particular the hydrochloride, in an amount (in chlorpromazine) of    from 12.5 mg to 600 mg; prochlorperazine and pharmaceutically    acceptable salts and solvates thereof, in particular the dimaleate,    in an amount (in prochlorperazine) of from 2.5 mg to 30 mg;    metoclopramide and pharmaceutically acceptable salts and solvates    thereof, in particular the monohydrochloride monohydrate, in an    amount (in metoclopramide) of from 5 mg to 60 mg; bromopride and    pharmaceutically acceptable salts and solvates, in particular the    monohydrochloride and the dihydrochloride monohydrate, in an amount    (in bromopride) of from 5 mg to 60 mg; clebopride and    pharmaceutically acceptable salts and solvates thereof, in    particular the hydrogen malate and the hydrochloride monohydrate, in    an amount (in clebopride) of from 0.25 mg to 3 mg; levosulpiride, in    an amount of from 12.5 mg to 600 mg; alizapride and pharmaceutically    acceptable salts thereof, in particular the hydrochloride, in an    amount (in alizapride) of from 25 mg to 300 mg; trimethobenzamide    and pharmaceutically acceptable salts thereof such as the    monohydrochloride, in an amount (in trimethobenzamide) of from 50 mg    to 600 mg; meclizine (also called meclozine) and pharmaceutically    acceptable salts and solvates thereof, in an amount (in meclizine)    of from 6.25 mg to 300 mg; promethazine and pharmaceutically    acceptable salts and solvates thereof, in particular the    hydrochloride, in an amount (in promethazine) of from 12.5 mg to 150    mg; dronabinol in an amount of from 1.25 mg to 60 mg; nabilone, in    an amount of from 0.5 mg to 6 mg; aprepitant, in an amount of from    20 mg to 750 mg; netupitant, in an amount of from 150 mg to 1800 mg;    rolapitant, in an amount of from 30 mg to 360 mg; and casopitant;    and-   (d) a pharmaceutical composition comprising a nsPAChA selected from    the group consisting of solifenacin and pharmaceutically acceptable    salts thereof, in an amount that is equivalent to from 10 mg to 30    mg of solifenacin succinate, in admixture with a pharmaceutical    carrier or vehicle,-   in admixture with a pharmaceutical carrier or vehicle.

Preferably, the naAEA is selected from the group consisting of alosetronhydrochloride, in an amount (in alosetron) of from 0.25 mg to 6 mg;azasetron hydrochloride, in an amount (in azasetron) of from 5 mg to 60mg; dolasetron mesylate, in an amount (in dolasetron) of from 25 mg to600 mg; granisetron hydrochloride, in an amount (in granisetron) of from0.5 mg to 6 mg; ondansetron hydrochloride dihydrate, in an amount (inondansetron) of from 2 mg to 64 mg; palonosetron hydrochloride, in anamount (in palonosetron) of from 0.25 mg to 3 mg; ramosetronhydrochloride, in an amount (in ramosetron) of from 0.0125 mg to 0.3 mg,tropisetron hydrochloride, in an amount (in tropisetron) of from 2.5 mgto 30 mg; domperidone and pharmaceutically acceptable salts and solvatesthereof, in an amount (in domperidone) of from 5 mg to 60 mg;haloperidol, in an amount of from 0.5 mg to 60 mg; chlorpromazinehydrochloride, in an amount (in chlorpromazine) of from 12.5 mg to 600mg; prochlorperazine dimaleate, in an amount (in prochlorperazine) offrom 2.5 mg to 30 mg; metoclopramide monohydrochloride monohydrate, inan amount (in metoclopramide) of from 5 mg to 60 mg; bromopridemonohydrochloride or dihydrochloride monohydrate, in an amount (inbromopride) of from 5 mg to 60 mg; clebopride hydrogen malate orhydrochloride monohydrate, in an amount (in clebopride) of from 0.25 mgto 3 mg; levosulpiride, in an amount of from 12.5 mg to 600 mg;alizapride hydrochloride, in an amount (in alizapride) of from 25 mg to300 mg; trimethobenzamide monohydrochloride, in an amount (intrimethobenzamide) of from 50 mg to 600 mg; meclizine (also calledmeclozine) and pharmaceutically acceptable salts and solvates thereof,in an amount (in meclizine) of from 6.25 mg to 300 mg; promethazinehydrochloride, in an amount (in promethazine) of from 12.5 mg to 150 mg;dronabinol in an amount of from 1.25 mg to 60 mg; nabilone, in an amountof from 0.5 mg to 6 mg; aprepitant, in an amount of from 20 mg to 750mg; netupitant, in an amount of from 150 mg to 1800 mg; rolapitant, inan amount of from 30 mg to 360 mg; and casopitant in an amount of from25 mg to 300 mg.

The Component (a/c) may be the brand memantine/donepezil fixed-dosecombination, as its brand preparation Namzaric®, in its 7mg-memantine/10 mg-donepezil presentation that may be used in multipleunit forms per each administration, when a 30 mg or 40 mg of donepezilhydrochloride dose is required.

Component (b) may be the brand palonosetron/netupitant (Akynzeo®)consisting of a capsule containing netupitant in an amount of 300 mg andpalonosetron hydrochloride in an amount (in palonosetron) of 0.5 mg.

In a further fourth embodiment, the invention provides a pharmaceuticalcombination comprising

-   (a/c) a fixed-dose combination that is a pharmaceutical composition    comprising or consisting essentially of    -   (a) memantine or a pharmaceutically acceptable salt thereof; and    -   (c) donepezil or a pharmaceutically acceptable salt thereof, in        admixture with a pharmaceutical carrier or vehicle; and-   (b) a pharmaceutical composition in dosage unit form comprising or    consisting essentially of solifenacin or a pharmaceutically    acceptable salt thereof in admixture with a pharmaceutical carrier.

According to an advantageous aspect of this fourth embodiment, theinvention provides a combination comprising:

-   (a/c) a fixed-dose combination that is a pharmaceutical composition    comprising or consisting essentially of    -   (a) a memantine or a pharmaceutically acceptable salt thereof,        preferably the hydrochloride thereof in an amount of from 5 mg        to 30 mg; and    -   (c) donepezil or a pharmaceutically acceptable salt thereof,        preferably the hydrochloride thereof in an amount of from 10 mg        to 92 mg, in admixture with a pharmaceutical carrier or vehicle;        and-   (b) a pharmaceutical composition in dosage unit form comprising or    consisting essentially of solifenacin or a pharmaceutically    acceptable salt thereof, preferably the succinate thereof in an    amount of from 10 mg to 30 mg,    in admixture with a pharmaceutical carrier or vehicle.

In a preferred combination according to this fourth embodiment, theComponent (a/c) comprises memantine hydrochloride, in an amount of from7 mg to 28 mg; and donepezil hydrochloride, in an amount of from 10 mgto 70 mg, normally from 20 mg to 70 mg; and the Component (b) issolifenacin succinate, in an amount of from 15 mg to 25 mg.

This memantine/donepezil fixed dose combination is also available as abrand preparation (Namzaric®), consisting of memantine hydrochlorideextended-release/donepezil hydrochloride fixed-dose combination, when a10-mg donepezil dose is required.

Said donepezil or pharmaceutically acceptable salt thereof isadministered at a daily dose that is equivalent to from 20 mg to 92 mgdonepezil hydrochloride.

Preferably, this memantine/solifenacin combination is a memantinehydrochloride/solifenacin succinate combination for use in combinationwith a pharmaceutical composition comprising donepezil hydrochloride, inan amount of from 20 mg to 92 mg, in admixture with a pharmaceuticalcarrier or vehicle, administered once per day.

An advantageous composition according to this embodiment consists of

-   -   Layer A, comprising from 7 mg to 28 mg of memantine        hydrochloride Component (a) in admixture with a pharmaceutical        carrier or vehicle in a ER formulation; and    -   Layer B, comprising from 10 mg to 30 mg of solifenacin succinate        Component (b), in admixture with a pharmaceutical carrier or        vehicle in an IR-formulation,        said composition being destined to be administered once per day,        in combination with a pharmaceutical composition comprising from        20 mg to 92 mg, advantageously from 40 mg to 92 mg, normally        from 40 mg to 70 mg, of donepezil hydrochloride, also destined        to be administered once per day.

Carriers or vehicles and vehicles for ER tablets include retardantmaterials such as is acrylic and methacrylic acid polymers andcopolymers; cellulose derivatives such as hydroxypropylmethylcellulose,hydroxyethylcellulose, hydroxypropylethylcellulose,hydroxypropylcelluloses, methylcellulose, ethylcellulose, or sodiumcarboxymethylcellulose; gums; waxes; glycerides or aliphatic alcohols ora mixture thereof.

According to another embodiment, the invention provides the herein aboveillustrated memantine/solifenacin combination comprising

-   (c) memantine or a pharmaceutically acceptable salt thereof; and-   (d) solifenacin or a pharmaceutically acceptable salt thereof,    for use for treating hypocholinergic disorders in further    combination with donepezil or a pharmaceutically acceptable salt    thereof in an amount that is equivalent to from 20 mg to 92 mg of    donepezil hydrochloride, as a single dose.

Thanks to the solifenacin/memantine synergism, said donepezilhydrochloride amount may advantageously be of from 40 mg to 92 mg orfrom 40 mg to 70 mg, as a single daily dose, with substantially improvedtherapeutic response.

For the intended use, each of the Components (a) and (b) are formulatedin a pharmaceutical composition. Thus, in the above combination,memantine or a pharmaceutically acceptable salt is in a pharmaceuticalcomposition, preferably in dosage unit form, comprising said memantineor pharmaceutically acceptable salt thereof, in an amount that isequivalent to from 5 mg to 30 mg of memantine hydrochloride, inadmixture with a pharmaceutical carrier or vehicle; and said solifenacinor pharmaceutically acceptable salt thereof is in a pharmaceuticalcomposition, preferably in dosage unit form, comprising said solifenacinor pharmaceutically acceptable salt thereof, in an amount that isequivalent to from 10 mg to 30 mg of solifenacin succinate.

Component (a) and Component (b) are advantageously combined in a fixeddose combination for the simultaneous administration of the twoComponents. These fixed-dose combinations are in pharmaceutical unitforms wherein Component (a) and Component (b) are present, together orseparately, in admixture with a pharmaceutical carrier or vehicle. Inthese unit forms, memantine or a pharmaceutically acceptable saltthereof, especially its hydrochloride, and solifenacin or apharmaceutically acceptable salt thereof, especially its succinate, arepresent in an IR- or ER-formulation.

According to a preferred embodiment, the invention provides acombination comprising

-   (a) a pharmaceutical composition comprising memantine or a    pharmaceutically acceptable salt thereof, in an amount that is    equivalent to from 5 mg to 30 mg of memantine hydrochloride, in    admixture with a pharmaceutical carrier or vehicle; and-   (b) a pharmaceutical composition comprising solifenacin or a    pharmaceutically acceptable salt thereof, in an amount that is    equivalent to from 10 mg to 30 mg of solifenacin succinate, in    admixture with a pharmaceutical carrier or vehicle,    for use for treating Alzheimer type dementia in further combination    with a pharmaceutical composition comprising donepezil or a    pharmaceutically acceptable salt thereof.

Said donepezil or pharmaceutically acceptable salt thereof isadministered at a daily dose that is equivalent to from 20 mg to 92 mgdonepezil hydrochloride.

Preferably, this memantine/solifenacin combination is a memantinehydrochloride/solifenacin succinate combination for use in combinationwith a pharmaceutical composition comprising donepezil hydrochloride, inan amount of from 20 mg to 92 mg, in admixture with a pharmaceuticalcarrier or vehicle, administered once per day.

Thanks to the solifenacin/memantine synergism, said donepezilhydrochloride amount may advantageously be of from 40 mg to 92 mg orfrom 40 mg to 70 mg, as a single daily dose, with substantially improvedtherapeutic response.

According to a this preferred embodiment, memantine or apharmaceutically acceptable salt thereof and solifenacin or apharmaceutically acceptable salt thereof are in a fixed-dose combinationas illustrated herein above, Said fixed-dose combination essentiallyconsists of a pharmaceutical composition, preferably in dosage unitform, comprising said memantine or pharmaceutically acceptable saltthereof, in an amount that is equivalent to from 5 mg to 30 mg; and saidsolifenacin or pharmaceutically acceptable salt thereof, in an amountthat is equivalent to from 10 to 30 mg, in admixture with apharmaceutical carrier or vehicle.

The memantine/solifenacin fixed-dose combination according to thispreferred embodiment is useful for an easy and safe treatment ofhypocholinergic disorders in combination with a pharmaceuticalcomposition comprising donepezil or a pharmaceutically acceptable saltthereof, in an amount that is equivalent to from 20 mg to 92 mg,preferably from 40 mg to 92 mg, normally from 40 mg to 70 mg ofdonepezil hydrochloride.

According to another embodiment, the present invention provides afixed-dose combination essentially consisting of a pharmaceuticalcomposition comprising, as Components,

-   (a) memantine or a pharmaceutically acceptable salt thereof, in an    amount that is equivalent to from 5 mg to 30 mg of memantine    hydrochloride;-   (b) solifenacin or a pharmaceutical acceptable salt thereof, in an    amount that is equivalent to from 10 mg to 30 mg of solifenacin    succinate; and-   (c) donepezil or a pharmaceutically acceptable salt thereof, in an    amount that is equivalent to from 20 mg to 92 mg of donepezil    hydrochloride, in admixture with a pharmaceutical carrier or    vehicle.

According to an advantageous aspect of this embodiment, thepharmaceutical composition comprises memantine hydrochloride, in anamount of from 5 mg to 30 mg, solifenacin succinate, in an amount offrom 10 mg to 30 mg and donepezil hydrochloride, in an amount of from 40kg to 92 mg, normally from 40 mg to 70 mg.

A pharmaceutical unit form comprising (a) memantine hydrochloride, in apharmaceutical composition comprising said memantine hydrochloride in anamount of from 5 mg to 30 mg, in admixture with a pharmaceutical carrierin extended-release formulation; and (b) solifenacin succinate, in apharmaceutical composition comprising said solifenacin succinate in anamount of from 10 mg to 30 mg, in admixture with a pharmaceuticalcarrier or vehicle in an immediate release formulation, is particularlyadvantageous.

For oral use, Component (a) and Component (b) are in compositions inadmixture with pharmaceutical excipients in known formulations whereinsaid Components are mixed together or separated, for example in twotablets introduced in a capsule, as described in as described in GB1204580, the disclosure of which is incorporated herein for reference,or in a two-compartment capsule or in a multilayer (bilayer) tabletwherein the two components are both in IR form or wherein the memantinepharmaceutically acceptable salt, especially the hydrochloride, is inER-form, and the solifenacin pharmaceutically acceptable salt,especially the succinate thereof, is in IR-form, according to thetechnologies disclosed in U.S. Pat. No. 7,303,761 or 8,802,143, thedisclosures of which are incorporated herein in their entirety forreference.

Component (a) and Component (b) may also be present in form of one oftheir complexes with a cyclodextrin, for example α-cyclodextrin,β-cyclodextrin, γ-cyclodextrin, 2-hydroxypropyl-β-cyclodextrin ormethyl-β-cyclodextrin.

Component (a) and Component (b) may also be formulated in the form ofmicrocapsules, optionally with one or more carriers or vehicles oradditives.

For oral administration, Component (a) and Component (b), together orseparately, are formulated by mixing the active ingredient withconventional pharmaceutical acceptable carriers or vehicles enablingsaid active ingredients to be formulated in tablets, dragees, orallydisintegrating tablets, capsules, liquid solutions or suspensions,syrups and the like.

The composition according to the present invention may be in form of acapsule containing two tablets as described herein above, one of themcomprising Component (a) and the other comprising Component (b).

The composition of memantine/solifenacin may be formulated in tablets inwhich one or both of the two components is in controlled-release form,for example as a dispersion of said component inhydroxypropyl-methyl-cellulose or in a film-coated microgranule.

Advantageously, memantine, preferably memantine hydrochloride in anER-formulation and in an amount of 7 mg to 28 mg, is in the core, andsolifenacin, preferably solifenacin succinate, in IR-formulation and inan amount of from 10 mg to 30 mg, is in the outer layer in a bilayertablet in which, both the core and the outer layer may be coated with afilm.

The memantine/solifenacin fixed-dose combination according to thepresent invention may be also formulated in a bi-layer tablet, the firstlayer containing memantine or a pharmaceutically acceptable salt thereofand the second one containing solifenacin or a pharmaceuticallyacceptable salt thereof. A third layer, free of active substances, couldbe inserted between said first and said second layer.

In said fixed dose combination, the retardant material of said firstlayer and the immediate release carrier second layer are two elementsselected in order to allow respectively an extended (or sustained)release delivery of the memantine pharmaceutically acceptable salts,normally the hydrochloride, and to provide the solifenacinpharmaceutically acceptable salt, normally the succinate, in admixturewith a pharmaceutical carrier for immediate release, for exampleaccording to the technologies described in U.S. Pat. No. 7,303,761 or inU.S. Pat. No. 8,802,143, the disclosures of which are incorporatedherein in their entirety.

According to a fifth embodiment, the invention provides a pharmaceuticalcombination essentially consisting of

-   (a/d) a fixed-dose combination essentially consisting of a    pharmaceutical composition in dosage unit form comprising    -   (a) memantine or a pharmaceutically acceptable salt thereof, in        amount that is equivalent to from 5 mg to 30 mg of memantine        hydrochloride; and    -   (d) a nsPAChA selected from the group consisting of solifenacin        and pharmaceutically acceptable salts thereof, in an amount that        is equivalent to from 10 mg to 30 mg of solifenacin succinate;    -   in admixture with a pharmaceutical carrier or vehicle;    -   (b) a pharmaceutical composition in dosage unit form comprising        a naAEA; and    -   (c) a pharmaceutical composition in dosage unit form comprising        a ChEI selected from the group consisting of donepezil and        pharmaceutically acceptable salts thereof, in an amount that is        equivalent to from 20 mg to 92 mg of donepezil hydrochloride, in        admixture with a pharmaceutical carrier or vehicle.

An advantageous aspect of this fifth embodiment provides a combinationessentially consisting of

-   (a/d) a fixed-dose combination essentially consisting of a    pharmaceutical composition in dosage unit form comprising    -   (a) memantine or a pharmaceutically acceptable salt thereof, in        amount that is equivalent to from 7 mg to 28 mg of memantine        hydrochloride; and    -   (d) solifenacin or a pharmaceutically acceptable salt thereof,        in an amount that is equivalent to from 10 mg to 30 mg of        solifenacin succinate,    -   in admixture with a pharmaceutical carrier or vehicle; and-   (b) a pharmaceutical composition in dosage unit form comprising a    naAEA selected from the group consisting of alosetron and    pharmaceutically acceptable salts and solvates thereof, in    particular the hydrochloride, in an amount (in alosetron) of from    0.25 mg to 6 mg; azasetron and pharmaceutically acceptable salts and    solvates thereof, in particular the hydrochloride, in an amount (in    azasetron) of from 5 mg to 60 mg; dolasetron and pharmaceutically    acceptable salts and solvates thereof, in particular the mesylate,    in an amount (in dolasetron) of from 25 mg to 600 mg; granisetron    and pharmaceutically acceptable salts and solvates thereof, in    particular the hydrochloride, in an amount (in granisetron) of from    0.5 mg to 6 mg; ondansetron and pharmaceutically acceptable salts    and solvates thereof, in particular the hydrochloride dihydrate, in    an amount (in ondansetron) of from 2 mg to 64 mg; palonosetron and    pharmaceutically acceptable salts and solvated thereof, in    particular its hydrochloride, in an amount (in palonosetron) of from    0.25 mg to 3 mg; ramosetron and pharmaceutically acceptable salts    and solvates thereof, in particular its hydrochloride, in an amount    (in ramosetron) of from 0.0125 mg to 0.3 mg; tropisetron and    pharmaceutically acceptable salts and solvates thereof, in    particular the hydrochloride, in an amount of from 2.5 mg to 30 mg;    domperidone and pharmaceutically acceptable salts and solvates    thereof, in an amount (in domperidone) of from 5 mg to 60 mg;    haloperidol, in an amount of from 0.5 mg to 60 mg; chlorpromazine    and pharmaceutically acceptable salts and solvates thereof, in    particular the hydrochloride, in an amount (in chlorpromazine) of    from 12.5 mg to 600 mg; prochlorperazine and pharmaceutically    acceptable salts and solvates thereof, in particular the dimaleate,    in an amount (in prochlorperazine) of from 2.5 mg to 30 mg;    metoclopramide and pharmaceutically acceptable salts and solvates    thereof, in particular the monohydrochloride monohydrate, in an    amount (in metoclopramide) of from 5 mg to 60 mg; bromopride and    pharmaceutically acceptable salts and solvates, in particular the    monohydrochloride and the dihydrochloride monohydrate, in an amount    (in bromopride) of from 5 mg to 60 mg; clebopride and    pharmaceutically acceptable salts and solvates thereof, in    particular the hydrogen malate and the hydrochloride monohydrate, in    an amount (in clebopride) of from 0.25 mg to 3 mg; levosulpiride, in    an amount of from 12.5 mg to 600 mg; alizapride and pharmaceutically    acceptable salts thereof, in particular the hydrochloride, in an    amount (in alizapride) of from 25 mg to 300 mg; trimethobenzamide    and pharmaceutically acceptable salts thereof such as the    monohydrochloride, in an amount (in trimethobenzamide) of from 50 mg    to 600 mg; meclizine (also called meclozine) and pharmaceutically    acceptable salts and solvates thereof, in an amount (in meclizine)    of from 6.25 mg to 300 mg; promethazine and pharmaceutically    acceptable salts and solvates thereof, in particular the    hydrochloride, in an amount (in promethazine) of from 12.5 mg to 150    mg; dronabinol in an amount of from 1.25 mg to 60 mg; nabilone, in    an amount of from 0.5 mg to 6 mg; aprepitant, in an amount of from    20 mg to 750 mg; netupitant, in an amount of from 150 mg to 1800 mg;    rolapitant, in an amount of from 30 mg to 360 mg; and casopitant, in    an amount of from 25 mg to 300 mg, in admixture with a    pharmaceutical carrier or vehicle; and-   (c) donepezil or a pharmaceutically acceptable salts thereof, in an    amount that is equivalent to from 25 mg to 92 mg or from 40 mg to 70    mg of donepezil hydrochloride, in a pharmaceutical composition in    admixture with a pharmaceutical carrier or vehicle.

Preferably, the naAEA Component (b) in the (b/c) fixed-dose combinationis selected from the group consisting of alosetron hydrochloride, in anamount (in alosetron) of from 0.25 mg to 6 mg; azasetron hydrochloride,in an amount (in azasetron) of from 5 mg to 60 mg; dolasetron mesylate,in an amount (in dolasetron) of from 25 mg to 600 mg; granisetronhydrochloride, in an amount (in granisetron) of from 0.5 mg to 6 mg;ondansetron hydrochloride dihydrate, in an amount (in ondansetron) offrom 2 mg to 64 mg; palonosetron hydrochloride, in an amount (inpalonosetron) of from 0.25 mg to 3 mg; ramosetron hydrochloride, in anamount (in ramosetron) of from 0.0125 mg to 0.3 mg, tropisetronhydrochloride, in an amount (in tropisetron) of from 2.5 mg to 30 mg;domperidone and pharmaceutically acceptable salts and solvates thereof,in an amount (in domperidone) of from 5 mg to 60 mg; haloperidol, in anamount of from 0.5 mg to 60 mg; chlorpromazine hydrochloride, in anamount (in chlorpromazine) of from 12.5 mg to 600 mg; prochlorperazinedimaleate, in an amount (in prochlorperazine) of from 2.5 mg to 30 mg;metoclopramide monohydrochloride monohydrate, in an amount (inmetoclopramide) of from 5 mg to 60 mg; bromopride monohydrochloride ordihydrochloride monohydrate, in an amount (in bromopride) of from 5 mgto 60 mg; clebopride hydrogen malate or hydrochloride monohydrate, in anamount (in clebopride) of from 0.25 mg to 3 mg; levosulpiride, in anamount of from 12.5 mg to 600 mg; alizapride hydrochloride, in an amount(in alizapride) of from 25 mg to 300 mg; trimethobenzamidemonohydrochloride, in an amount (in trimethobenzamide) of from 50 mg to600 mg; meclizine (also called meclozine) and pharmaceuticallyacceptable salts and solvates thereof, in an amount (in meclizine) offrom 6.25 mg to 300 mg; promethazine hydrochloride, in an amount (inpromethazine) of from 12.5 mg to 150 mg; dronabinol in an amount of from1.25 mg to 60 mg; nabilone, in an amount of from 0.5 mg to 6 mg;aprepitant, in an amount of from 20 mg to 750 mg; netupitant, in anamount of from 150 mg to 1800 mg; rolapitant, in an amount of from 30 mgto 360 mg; and casopitant, in an amount of from 25 mg to 300 mg.

In a further fifth embodiment, the present invention provides afixed-dose combination essentially consisting of a pharmaceuticalcomposition comprising, as Components,

-   (d) memantine or a pharmaceutically acceptable salt thereof, in an    amount that is equivalent to from 5 mg to 30 mg of memantine    hydrochloride;-   (e) solifenacin or a pharmaceutical acceptable salt thereof, in an    amount that is equivalent to from 10 mg to 30 mg of solifenacin    succinate, advantageously from 15 mg to 25 mg, preferably of 15 mg;    and-   (f) donepezil or a pharmaceutically acceptable salt thereof, in an    amount that is equivalent to from 10 mg to 92 mg, preferably from 20    mg to 92 mg, normally from 10 mg to 70 mg, preferably from 20 mg to    70 mg, of donepezil hydrochloride,    in admixture with a pharmaceutical carrier or vehicle.

According to an advantageous aspect of this embodiment, thepharmaceutical composition comprises memantine hydrochloride, in anamount of from 5 mg to 30 mg, solifenacin succinate, in an amount offrom 10 mg to 30 mg, advantageously from 15 mg to 25 mg, and donepezilhydrochloride, in an amount of from 10 mg to 92 mg, preferably from 20mg to 92 mg, normally from 10 mg to 70 mg, preferably from 20 mg to 70mg or from 40 mg to 70 mg.

A sixth embodiment of the present invention provides a combinationessentially consisting of

-   (a) a pharmaceutical composition in dosage unit form comprising    memantine or a pharmaceutically acceptable salt thereof, in amount    that is equivalent to from 5 mg to 30 mg of memantine hydrochloride;-   (b/c) a fixed dose combination consisting of a pharmaceutical    composition in dosage unit form comprising    -   (a) a naAEA; and    -   (b) donepezil or a pharmaceutically acceptable salts thereof, in        an amount that is equivalent to from 20 mg to 92 mg of donepezil        hydrochloride,    -   in admixture with a pharmaceutical carrier or vehicle; and    -   (c) a pharmaceutical composition comprising a nsPAChA selected        from the group consisting of solifenacin and pharmaceutically        acceptable salts thereof, in an amount that is equivalent to        from 10 mg to 30 mg of solifenacin succinate, in admixture with        a pharmaceutical carrier or vehicle.

Normally, the naAEA component (b) is selected from the group consistingof (b1) 5HT3-antagonists; (b2) DA-antagonists; (b3) H1-antagonists; (b4)cannabinoids; (b5) NK1-antagonists.

Among the above (b1)-(b5) naAEA, a naAEA selected from the groupconsisting of alosetron and pharmaceutically acceptable salts andsolvates thereof, in particular the hydrochloride, in an amount (inalosetron) of from 0.25 mg to 6 mg; azasetron and pharmaceuticallyacceptable salts and solvates thereof, in particular the hydrochloride,in an amount (in azasetron) of from 5 mg to 60 mg; dolasetron andpharmaceutically acceptable salts and solvates thereof, in particularthe mesylate, in an amount (in dolasetron) of from 25 mg to 600 mg;granisetron and pharmaceutically acceptable salts and solvates thereof,in particular the hydrochloride, in an amount (in granisetron) of from0.5 mg to 6 mg; ondansetron and pharmaceutically acceptable salts andsolvates thereof, in particular the hydrochloride dihydrate, in anamount (in ondansetron) of from 2 mg to 64 mg; palonosetron andpharmaceutically acceptable salts and solvated thereof, in particularits hydrochloride, in an amount (in palonosetron) of from 0.25 mg to 3mg; ramosetron and pharmaceutically acceptable salts and solvatesthereof, in particular its hydrochloride, in an amount (in ramosetron)of from 0.0125 mg to 0.3 mg; tropisetron and pharmaceutically acceptablesalts and solvates thereof, in particular the hydrochloride, in anamount of from 2.5 mg to 30 mg; domperidone and pharmaceuticallyacceptable salts and solvates thereof, in an amount (in domperidone) offrom 5 mg to 60 mg; haloperidol, in an amount of from 0.5 mg to 60 mg;chlorpromazine and pharmaceutically acceptable salts and solvatesthereof, in particular the hydrochloride, in an amount (inchlorpromazine) of from 12.5 mg to 600 mg; prochlorperazine andpharmaceutically acceptable salts and solvates thereof, in particularthe dimaleate, in an amount (in prochlorperazine) of from 2.5 mg to 30mg; metoclopramide and pharmaceutically acceptable salts and solvatesthereof, in particular the monohydrochloride monohydrate, in an amount(in metoclopramide) of from 5 mg to 60 mg; bromopride andpharmaceutically acceptable salts and solvates, in particular themonohydrochloride and the dihydrochloride monohydrate, in an amount (inbromopride) of from 5 mg to 60 mg; clebopride and pharmaceuticallyacceptable salts and solvates thereof, in particular the hydrogen malateand the hydrochloride monohydrate, in an amount (in clebopride) of from0.25 mg to 3 mg; levosulpiride, in an amount of from 12.5 mg to 600 mg;alizapride and pharmaceutically acceptable salts thereof, in particularthe hydrochloride, in an amount (in alizapride) of from 25 mg to 300 mg;trimethobenzamide and pharmaceutically acceptable salts thereof such asthe monohydrochloride, in an amount (in trimethobenzamide) of from 50 mgto 600 mg; meclizine (also called meclozine) and pharmaceuticallyacceptable salts and solvates thereof, in an amount (in meclizine) offrom 6.25 mg to 300 mg; promethazine and pharmaceutically acceptablesalts and solvates thereof, in particular the hydrochloride, in anamount (in promethazine) of from 12.5 mg to 150 mg; dronabinol in anamount of from 1.25 mg to 60 mg; nabilone, in an amount of from 0.5 mgto 6 mg; aprepitant, in an amount of from 20 mg to 750 mg; netupitant,in an amount of from 150 mg to 1800 mg; rolapitant, in an amount of from30 mg to 360 mg; and casopitant, in an amount of from 25 mg to 300 mg,is particularly advantageous.

Preferably, in the pharmaceutical composition Component (b), the naAEAis selected from the group consisting of alosetron hydrochloride, in anamount (in alosetron) of from 0.25 mg to 6 mg; azasetron hydrochloride,in an amount (in azasetron) of from 5 mg to 60 mg; dolasetron mesylate,in an amount (in dolasetron) of from 25 mg to 600 mg; granisetronhydrochloride, in an amount (in granisetron) of from 0.5 mg to 6 mg;ondansetron hydrochloride dihydrate, in an amount (in ondansetron) offrom 2 mg to 64 mg; palonosetron hydrochloride, in an amount (inpalonosetron) of from 0.25 mg to 3 mg; ramosetron hydrochloride, in anamount (in ramosetron) of from 0.0125 mg to 0.3 mg, tropisetronhydrochloride, in an amount (in tropisetron) of from 2.5 mg to 30 mg;domperidone and pharmaceutically acceptable salts and solvates thereof,in an amount (in domperidone) of from 5 mg to 60 mg; haloperidol, in anamount of from 0.5 mg to 60 mg; chlorpromazine hydrochloride, in anamount (in chlorpromazine) of from 12.5 mg to 600 mg; prochlorperazinedimaleate, in an amount (in prochlorperazine) of from 2.5 mg to 30 mg;metoclopramide monohydrochloride monohydrate, in an amount (inmetoclopramide) of from 5 mg to 60 mg; bromopride monohydrochloride ordihydrochloride monohydrate, in an amount (in bromopride) of from 5 mgto 60 mg; clebopride hydrogen malate or hydrochloride monohydrate, in anamount (in clebopride) of from 0.25 mg to 3 mg; levosulpiride, in anamount of from 12.5 mg to 600 mg; alizapride hydrochloride, in an amount(in alizapride) of from 25 mg to 300 mg; trimethobenzamidemonohydrochloride, in an amount (in trimethobenzamide) of from 50 mg to600 mg; meclizine (also called meclozine) and pharmaceuticallyacceptable salts and solvates thereof, in an amount (in meclizine) offrom 6.25 mg to 300 mg; promethazine hydrochloride, in an amount (inpromethazine) of from 12.5 mg to 150 mg; dronabinol in an amount of from1.25 mg to 60 mg; nabilone, in an amount of from 0.5 mg to 6 mg;aprepitant, in an amount of from 20 mg to 750 mg; netupitant, in anamount of from 150 mg to 1800 mg; rolapitant, in an amount of from 30 mgto 360 mg; and casopitant, in an amount of from 25 mg to 300 mg.

The ChEI/nsPAChA Component (c/d) of this sixth embodiment is illustratedin WO 2009/120227 (see also U.S. Pat. No. 9,044,472) and in WO 14/039627(see also US 2015/0231122), the disclosures of which are incorporatedherein in their entirety by reference.

Component (b) may be the brand palonosetron/netupitant (Akynzeo®)consisting of a capsule containing netupitant in an amount of 300 mg andpalonosetron hydrochloride in an amount (in palonosetron) of 0.5 mg.

A seventh embodiment of the present invention provides a combinationessentially consists of

-   (a) memantine or a pharmaceutically acceptable salt thereof, in    amount that is equivalent to from 5 mg to 30 mg of memantine    hydrochloride, in a pharmaceutical composition in dosage unit form,    in admixture with a pharmaceutical carrier or vehicle;-   (b) a naAEA selected from the group consisting of alosetron and    pharmaceutically acceptable salts and solvates thereof, in    particular the hydrochloride, in an amount (in alosetron) of from    0.25 mg to 6 mg; azasetron and pharmaceutically acceptable salts and    solvates thereof, in particular the hydrochloride, in an amount (in    azasetron) of from 5 mg to 60 mg; dolasetron and pharmaceutically    acceptable salts and solvates thereof, in particular the mesylate,    in an amount (in dolasetron) of from 25 mg to 600 mg; granisetron    and pharmaceutically acceptable salts and solvates thereof, in    particular the hydrochloride, in an amount (in granisetron) of from    0.5 mg to 6 mg; ondansetron and pharmaceutically acceptable salts    and solvates thereof, in particular the hydrochloride dihydrate, in    an amount (in ondansetron) of from 2 mg to 64 mg; palonosetron and    pharmaceutically acceptable salts and solvated thereof, in    particular its hydrochloride, in an amount (in palonosetron) of from    0.25 mg to 3 mg; ramosetron and pharmaceutically acceptable salts    and solvates thereof, in particular its hydrochloride, in an amount    (in ramosetron) of from 0.0125 mg to 0.3 mg; tropisetron and    pharmaceutically acceptable salts and solvates thereof, in    particular the hydrochloride, in an amount of from 2.5 mg to 30 mg;    domperidone and pharmaceutically acceptable salts and solvates    thereof, in an amount (in domperidone) of from 5 mg to 60 mg;    haloperidol, in an amount of from 0.5 mg to 60 mg; chlorpromazine    and pharmaceutically acceptable salts and solvates thereof, in    particular the hydrochloride, in an amount (in chlorpromazine) of    from 12.5 mg to 600 mg; prochlorperazine and pharmaceutically    acceptable salts and solvates thereof, in particular the dimaleate,    in an amount (in prochlorperazine) of from 2.5 mg to 30 mg;    metoclopramide and pharmaceutically acceptable salts and solvates    thereof, in particular the monohydrochloride monohydrate, in an    amount (in metoclopramide) of from 5 mg to 60 mg; bromopride and    pharmaceutically acceptable salts and solvates, in particular the    monohydrochloride and the dihydrochloride monohydrate, in an amount    (in bromopride) of from 5 mg to 60 mg; clebopride and    pharmaceutically acceptable salts and solvates thereof, in    particular the hydrogen malate and the hydrochloride monohydrate, in    an amount (in clebopride) of from 0.25 mg to 3 mg; levosulpiride, in    an amount of from 12.5 mg to 600 mg; alizapride and pharmaceutically    acceptable salts thereof, in particular the hydrochloride, in an    amount (in alizapride) of from 25 mg to 300 mg; trimethobenzamide    and pharmaceutically acceptable salts thereof such as the    monohydrochloride, in an amount (in trimethobenzamide) of from 50 mg    to 600 mg; meclizine (also called meclozine) and pharmaceutically    acceptable salts and solvates thereof, in an amount (in meclizine)    of from 6.25 mg to 300 mg; promethazine and pharmaceutically    acceptable salts and solvates thereof, in particular the    hydrochloride, in an amount (in promethazine) of from 12.5 mg to 150    mg; dronabinol in an amount of from 1.25 mg to 60 mg; nabilone, in    an amount of from 0.5 mg to 6 mg; aprepitant, in an amount of from    20 mg to 750 mg; netupitant, in an amount of from 150 mg to 1800 mg;    rolapitant, in an amount of from 30 mg to 360 mg; and casopitant, in    an amount of from 25 mg to 300 mg and-   (c/d) a fixed-dose combination consisting of a pharmaceutical    composition in dosage unit form comprising    -   (c) a ChEI selected from the group consisting of donepezil or a        pharmaceutically acceptable salts thereof, in an amount that is        equivalent to from 10 mg to 92 mg, preferably from 20 mg to 92        mg, normally from 10 mg to 70 mg, preferably from 20 mg to 70 mg        of donepezil hydrochloride; and    -   (d) nsPAChA selected from the group consisting of solifenacin        and pharmaceutically acceptable salts thereof, in an amount that        is equivalent to from 10 mg to 30 mg, advantageously from 15 mg        to 25 mg, preferably of 25 mg, of solifenacin succinate, in        admixture with a pharmaceutical carrier or vehicle,        in admixture with a pharmaceutical carrier or vehicle.

Preferably, in the above (c/d) fixed-dose combination, the ChEIComponent (c) is donepezil hydrochloride, in an amount of from 20 mg to92 mg, advantageously from 20 mg to 70 mg and the nsPAChA is solifenacinsuccinate, in an amount of from 10 mg to 30 mg, preferably from 15 mg to25 mg. As set forth above, in the case of particular necessities,especially for use in the titration phase of the therapy, the donepezilhydrochloride effective amount that is present in the above fixed-dosecombinations Component (c/d), may be from 10 mg to 50 mg, in particularof 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg.

An advantageous aspect of this seventh embodiment comprises:

-   (a) a pharmaceutical composition in dosage unit form comprising or    consisting essentially of memantine hydrochloride, in an amount of    from 7 mg to 28 mg in admixture with a pharmaceutical carrier or    vehicle in ER form    in admixture with a pharmaceutical carrier;-   (b) a pharmaceutical composition comprising a naAEA selected from    the group consisting of alosetron hydrochloride, in an amount (in    alosetron) of from 0.25 mg to 6 mg; azasetron hydrochloride, in an    amount (in azasetron) of from 5 mg to 60 mg; dolasetron mesylate, in    an amount (in dolasetron) of from 25 mg to 600 mg; granisetron    hydrochloride, in an amount (in granisetron) of from 0.5 mg to 6 mg;    ondansetron hydrochloride dihydrate, in an amount (in ondansetron)    of from 2 mg to 64 mg; palonosetron hydrochloride, in an amount (in    palonosetron) of from 0.25 mg to 3 mg; ramosetron hydrochloride, in    an amount (in ramosetron) of from 0.0125 mg to 0.3 mg, tropisetron    hydrochloride, in an amount (in tropisetron) of from 2.5 mg to 30    mg; domperidone and pharmaceutically acceptable salts and solvates    thereof, in an amount (in domperidone) of from 5 mg to 60 mg;    haloperidol, in an amount of from 0.5 mg to 60 mg; chlorpromazine    hydrochloride, in an amount (in chlorpromazine) of from 12.5 mg to    600 mg; prochlorperazine dimaleate, in an amount (in    prochlorperazine) of from 2.5 mg to 30 mg; metoclopramide    monohydrochloride monohydrate, in an amount (in metoclopramide) of    from 5 mg to 60 mg; bromopride monohydrochloride or dihydrochloride    monohydrate, in an amount (in bromopride) of from 5 mg to 60 mg;    clebopride hydrogen malate or hydrochloride monohydrate, in an    amount (in clebopride) of from 0.25 mg to 3 mg; levosulpiride, in an    amount of from 12.5 mg to 600 mg; alizapride hydrochloride, in an    amount (in alizapride) of from 25 mg to 300 mg; trimethobenzamide    monohydrochloride, in an amount (in trimethobenzamide) of from 50 mg    to 600 mg; meclizine (also called meclozine) and pharmaceutically    acceptable salts and solvates thereof, in an amount (in meclizine)    of from 6.25 mg to 300 mg; promethazine hydrochloride, in an amount    (in promethazine) of from 12.5 mg to 150 mg; dronabinol in an amount    of from 1.25 mg to 60 mg; nabilone, in an amount of from 0.5 mg to 6    mg; aprepitant, in an amount of from 20 mg to 750 mg; netupitant, in    an amount of from 150 mg to 1800 mg; rolapitant, in an amount of    from 30 mg to 360 mg; and casopitant, in an amount of from 25 mg to    300 mg,    in admixture with a pharmaceutical carrier or vehicle; and-   (c/d) a fixed-dose combination that is a pharmaceutical composition    comprising or consisting essentially of    -   (c) solifenacin succinate, in an amount of 15 mg; and    -   (d) donepezil hydrochloride, in an amount of from 10 mg to 50        mg, normally from 10 mg to 40 mg,    -   in admixture with a pharmaceutical carrier or vehicle, in        IR-form.

As set forth above, this composition is particularly useful in thetitration phase of the treatment of a patient suffering from ahypocholinergic disorder and also during the treatment of saiddisorders, for donepezil doses up to 50 mg single or/daily dose.

According to an advantageous aspect of this seventh embodiment, theinvention provides the above Component (c/d) as a pharmaceuticalcomposition in dosage unit form in a novel formulation wherein thepharmaceutical carrier allows that said solifenacin succinate anddonepezil hydrochloride do not interact each other.

In particular, donepezil hydrochloride and solifenacin succinate arepresent in specific percent amount and the pharmaceutical carriercomprises a diluent such as talc, powdered cellulose, lactose; adisaggregating agents such as microcrystalline cellulose, crospovidoneor a starch, for example maize or corn starch; a lubricant such asmagnesium or calcium stearate; and a binder, such as methyl cellulose,ethyl cellulose or hydroxypropyl methyl cellulose, each in specificpercent amounts.

Specifically, the pharmaceutical carrier comprises lactose as a diluent;corn starch as a disaggregating agent; magnesium stearate as a lubricantand hydroxypropyl methyl cellulose as a binder.

Preferably, the pharmaceutical unit form comprising the preferredcomposition according to this third embodiment of the present inventionis a coated tablet containing donepezil hydrochloride, in an amount offrom 10 mg to 50 mg and solifenacin succinate, in an amount of 15 mg, asactive ingredients, in the core, in admixture with a pharmaceuticalcarrier as defined above.

In particular, in the donepezil/solifenacin fixed-dose combinationComponent (c/d) essentially consists in a pharmaceutical composition ina dosage unit form consisting of a coated tablet comprising solifenacinsuccinate, in an amount of from 5.5% to 6.5%, donepezil hydrochloride,in an amount of from 4% to 20%; a diluent, in a amount of from 60% to82%, a disaggregating agent, in a amount of from 6.8% to 7.5%; and abinder, in an amount of from 1.9% to 2.5% the total weight of the core.The coating is a non-enteric, fast-dissolving layer that covers the coreaccording to known technologies. Normally, it is constituted by acellulose derivative such as methyl hydroxyethyl cellulose orhydroxypropyl methyl cellulose, a glycerol ester such as diacetin ortriacetin and a pigment such as titanium dioxide. Normally, the coatingis Opadry®, especially the White 03K18533 type.

A eight embodiment of the present invention provides a pharmaceuticalcombination comprising

-   (a/b) a fixed-dose combination consisting of a pharmaceutical    composition in dosage unit form comprising    -   (a) memantine or a pharmaceutically acceptable salt thereof, in        amount that is equivalent to from 5 mg to 30 mg of memantine        hydrochloride; and    -   (b) a naAEA selected from the group consisting of alosetron and        pharmaceutically acceptable salts and solvates thereof, in        particular the hydrochloride, in an amount (in alosetron) of        from 0.25 mg to 6 mg; azasetron and pharmaceutically acceptable        salts and solvates thereof, in particular the hydrochloride, in        an amount (in azasetron) of from 5 mg to 60 mg; dolasetron and        pharmaceutically acceptable salts and solvates thereof, in        particular the mesylate, in an amount (in dolasetron) of from 25        mg to 600 mg; granisetron and pharmaceutically acceptable salts        and solvates thereof, in particular the hydrochloride, in an        amount (in granisetron) of from 0.5 mg to 6 mg; ondansetron and        pharmaceutically acceptable salts and solvates thereof, in        particular the hydrochloride dihydrate, in an amount (in        ondansetron) of from 2 mg to 64 mg; palonosetron and        pharmaceutically acceptable salts and solvated thereof, in        particular its hydrochloride, in an amount (in palonosetron) of        from 0.25 mg to 3 mg; ramosetron and pharmaceutically acceptable        salts and solvates thereof, in particular its hydrochloride, in        an amount (in ramosetron) of from 0.0125 mg to 0.3 mg;        tropisetron and pharmaceutically acceptable salts and solvates        thereof, in particular the hydrochloride, in an amount of from        2.5 mg to 30 mg; domperidone and pharmaceutically acceptable        salts and solvates thereof, in an amount (in domperidone) of        from 5 mg to 60 mg; haloperidol, in an amount of from 0.5 mg to        60 mg; chlorpromazine and pharmaceutically acceptable salts and        solvates thereof, in particular the hydrochloride, in an amount        (in chlorpromazine) of from 12.5 mg to 600 mg; prochlorperazine        and pharmaceutically acceptable salts and solvates thereof, in        particular the dimaleate, in an amount (in prochlorperazine) of        from 2.5 mg to 30 mg; metoclopramide and pharmaceutically        acceptable salts and solvates thereof, in particular the        monohydrochloride monohydrate, in an amount (in metoclopramide)        of from 5 mg to 60 mg; bromopride and pharmaceutically        acceptable salts and solvates, in particular the        monohydrochloride and the dihydrochloride monohydrate, in an        amount (in bromopride) of from 5 mg to 60 mg; clebopride and        pharmaceutically acceptable salts and solvates thereof, in        particular the hydrogen malate and the hydrochloride        monohydrate, in an amount (in clebopride) of from 0.25 mg to 3        mg; levosulpiride, in an amount of from 12.5 mg to 600 mg;        alizapride and pharmaceutically acceptable salts thereof, in        particular the hydrochloride, in an amount (in alizapride) of        from 25 mg to 300 mg; trimethobenzamide and pharmaceutically        acceptable salts thereof such as the monohydrochloride, in an        amount (in trimethobenzamide) of from 50 mg to 600 mg; meclizine        (also called meclozine) and pharmaceutically acceptable salts        and solvates thereof, in an amount (in meclizine) of from 6.25        mg to 300 mg; promethazine and pharmaceutically acceptable salts        and solvates thereof, in particular the hydrochloride, in an        amount (in promethazine) of from 12.5 mg to 150 mg; dronabinol        in an amount of from 1.25 mg to 60 mg; nabilone, in an amount of        from 0.5 mg to 6 mg; aprepitant, in an amount of from 20 mg to        750 mg; netupitant, in an amount of from 150 mg to 1800 mg;        rolapitant, in an amount of from 30 mg to 360 mg; and        casopitant, in an amount of from 25 mg to 300 mg,        in admixture with a pharmaceutical carrier or vehicle; and-   (c/d) a fixed-dose combination consisting of a pharmaceutical    composition in dosage unit form comprising    -   (c) donepezil or a pharmaceutically acceptable salts thereof, in        an amount that is equivalent to from 10 mg to 92 mg, preferably        from 20 mg to 92 mg, normally from 10 mg to 70 mg, preferably        from 20 mg to 70 mg of donepezil hydrochloride; and    -   (d) a nsPAChA selected from the group consisting of solifenacin        and pharmaceutically acceptable salts thereof, in an amount that        is equivalent to from 10 mg to 30 mg, advantageously from 15 mg        to 25 mg, preferably of 15 mg of solifenacin succinate,        in admixture with a pharmaceutical carrier or vehicle.

According to an advantageous aspect of this eight embodiment, theComponent (a/b) is a pharmaceutical composition comprising (a) memantinehydrochloride, in an amount of from 5 mg to 30 mg, preferably from 7 mgto 28 mg; and (b); a naAEA selected from the group consisting ofgranisetron hydrochloride in an amount (in granisetron) of from 1 mg to3 mg; domperidone in an amount of from 10 mg to 30 mg; metoclopramidemonohydrochloride monohydrate in an amount (in metoclopramide) of from10 mg to 30 mg; aprepitant, in an amount of from 40 mg to 375 mg, inadmixture with a pharmaceutical carrier or vehicle.

According to a second advantageous aspect of this eight embodiment ofthe present invention the component (a/b) essentially consists of

-   (a) memantine or a pharmaceutically acceptable salt thereof, in    amount that is equivalent to from 5 mg to 30 mg of memantine    hydrochloride; and-   (b) a naAEA selected from the group consisting of ondansetron and    pharmaceutically acceptable salts and solvates thereof, in an amount    (in ondansetron) of from 4 mg to 64 mg,    in admixture with a pharmaceutical carrier or vehicle.

A specific component (a/b) according to this second advantageous aspectof this eight embodiment of the present invention essentially consistsof

-   (a) memantine or a pharmaceutically acceptable salt thereof, in    amount that is equivalent to from 5 mg to 10 mg of memantine    hydrochloride; and-   (b) a naAEA selected from the group consisting of ondansetron and    pharmaceutically acceptable salts and solvates thereof, in an amount    (in ondansetron) of from 4 mg to 32 mg,    in admixture with a pharmaceutical carrier or vehicle in an    IR-formulation.

A particularly preferred, specific Component (a/b) according to thissecond advantageous aspect of this eight embodiment of the presentinvention essentially consists of

-   (a) memantine or a pharmaceutically acceptable salt thereof, in    amount that is equivalent to from 7 mg to 28 mg of memantine    hydrochloride; and-   (d) a naAEA selected from the group consisting of ondansetron and    pharmaceutically acceptable salts and solvates thereof, in    particular the hydrochloride dihydrate, in an amount (in    ondansetron) of from 16 mg to 64 mg,    in admixture with a pharmaceutical carrier or vehicle in an    ER-formulation.

According to a ninth embodiment, the invention provides a combinationessentially consists of

-   (a/c) a fixed-dose combination consisting of a pharmaceutical    composition in dosage unit form comprising    -   (a) memantine or a pharmaceutically acceptable salt thereof, in        amount that is equivalent to from 5 mg to 30 mg of memantine        hydrochloride; and    -   (c) donepezil or a pharmaceutically acceptable salts thereof, in        an amount that is equivalent to from 10 mg to 92 mg, preferably        from 20 mg to 92 mg, normally from 10 mg to 70 mg, preferably        from 20 mg to 70 mg of donepezil hydrochloride,    -   in a pharmaceutical composition in admixture with a        pharmaceutical carrier or vehicle; and-   (b/d) a fixed-dose combination comprising    -   (b) a naAEA selected from the group consisting of alosetron and        pharmaceutically acceptable salts and solvates thereof, in        particular the hydrochloride, in an amount (in alosetron) of        from 0.25 mg to 6 mg; azasetron and pharmaceutically acceptable        salts and solvates thereof, in particular the hydrochloride, in        an amount (in azasetron) of from 5 mg to 60 mg; dolasetron and        pharmaceutically acceptable salts and solvates thereof, in        particular the mesylate, in an amount (in dolasetron) of from 25        mg to 600 mg; granisetron and pharmaceutically acceptable salts        and solvates thereof, in particular the hydrochloride, in an        amount (in granisetron) of from 0.5 mg to 6 mg; ondansetron and        pharmaceutically acceptable salts and solvates thereof, in        particular the hydrochloride dihydrate, in an amount (in        ondansetron) of from 2 mg to 64 mg; palonosetron and        pharmaceutically acceptable salts and solvated thereof, in        particular its hydrochloride, in an amount (in palonosetron) of        from 0.25 mg to 3 mg; ramosetron and pharmaceutically acceptable        salts and solvates thereof, in particular its hydrochloride, in        an amount (in ramosetron) of from 0.0125 mg to 0.3 mg;        tropisetron and pharmaceutically acceptable salts and solvates        thereof, in particular the hydrochloride, in an amount of from        2.5 mg to 30 mg; domperidone and pharmaceutically acceptable        salts and solvates thereof, in an amount (in domperidone) of        from 5 mg to 60 mg; haloperidol, in an amount of from 0.5 mg to        60 mg; chlorpromazine and pharmaceutically acceptable salts and        solvates thereof, in particular the hydrochloride, in an amount        (in chlorpromazine) of from 12.5 mg to 600 mg; prochlorperazine        and pharmaceutically acceptable salts and solvates thereof, in        particular the dimaleate, in an amount (in prochlorperazine) of        from 2.5 mg to 30 mg; metoclopramide and pharmaceutically        acceptable salts and solvates thereof, in particular the        monohydrochloride monohydrate, in an amount (in metoclopramide)        of from 5 mg to 60 mg; bromopride and pharmaceutically        acceptable salts and solvates, in particular the        monohydrochloride and the dihydrochloride monohydrate, in an        amount (in bromopride) of from 5 mg to 60 mg; clebopride and        pharmaceutically acceptable salts and solvates thereof, in        particular the hydrogen malate and the hydrochloride        monohydrate, in an amount (in clebopride) of from 0.25 mg to 3        mg; levosulpiride, in an amount of from 12.5 mg to 600 mg;        alizapride and pharmaceutically acceptable salts thereof, in        particular the hydrochloride, in an amount (in alizapride) of        from 25 mg to 300 mg; trimethobenzamide and pharmaceutically        acceptable salts thereof such as the monohydrochloride, in an        amount (in trimethobenzamide) of from 50 mg to 600 mg; meclizine        (also called meclozine) and pharmaceutically acceptable salts        and solvates thereof, in an amount (in meclizine) of from 6.25        mg to 300 mg; promethazine and pharmaceutically acceptable salts        and solvates thereof, in particular the hydrochloride, in an        amount (in promethazine) of from 12.5 mg to 150 mg; dronabinol        in an amount of from 1.25 mg to 60 mg; nabilone, in an amount of        from 0.5 mg to 6 mg; aprepitant, in an amount of from 20 mg to        750 mg; netupitant, in an amount of from 150 mg to 1800 mg;        rolapitant, in an amount of from 30 mg to 360 mg; and        casopitant, in an amount of from 25 mg to 300 mg; and-   (d) a nsPAChA selected from the group consisting of solifenacin and    pharmaceutically acceptable salts thereof, in an amount that is    equivalent to from 10 mg to 30, advantageously from 15 mg to 25 mg,    preferably of 15 mg of solifenacin succinate,    in admixture with a pharmaceutical carrier or vehicle.

In said (b/d) fixed dose combination, the naAEA Component (b) ispreferably selected from the group consisting of alosetronhydrochloride, in an amount (in alosetron) of from 0.25 mg to 6 mg;azasetron hydrochloride, in an amount (in azasetron) of from 5 mg to 60mg; dolasetron mesylate, in an amount (in dolasetron) of from 25 mg to600 mg; granisetron hydrochloride, in an amount (in granisetron) of from0.5 mg to 6 mg; ondansetron hydrochloride dihydrate, in an amount (inondansetron) of from 2 mg to 64 mg; palonosetron hydrochloride, in anamount (in palonosetron) of from 0.25 mg to 3 mg; ramosetronhydrochloride, in an amount (in ramosetron) of from 0.0125 mg to 0.3 mg,tropisetron hydrochloride, in an amount (in tropisetron) of from 2.5 mgto 30 mg; domperidone and pharmaceutically acceptable salts and solvatesthereof, in an amount (in domperidone) of from 5 mg to 60 mg;haloperidol, in an amount of from 0.5 mg to 60 mg; chlorpromazinehydrochloride, in an amount (in chlorpromazine) of from 12.5 mg to 600mg; prochlorperazine dimaleate, in an amount (in prochlorperazine) offrom 2.5 mg to 30 mg; metoclopramide monohydrochloride monohydrate, inan amount (in metoclopramide) of from 5 mg to 60 mg; bromopridemonohydrochloride or dihydrochloride monohydrate, in an amount (inbromopride) of from 5 mg to 60 mg; clebopride hydrogen malate orhydrochloride monohydrate, in an amount (in clebopride) of from 0.25 mgto 3 mg; levosulpiride, in an amount of from 12.5 mg to 600 mg;alizapride hydrochloride, in an amount (in alizapride) of from 25 mg to300 mg; trimethobenzamide monohydrochloride, in an amount (intrimethobenzamide) of from 50 mg to 600 mg; meclizine (also calledmeclozine) and pharmaceutically acceptable salts and solvates thereof,in an amount (in meclizine) of from 6.25 mg to 300 mg; promethazinehydrochloride, in an amount (in promethazine) of from 12.5 mg to 150 mg;dronabinol in an amount of from 1.25 mg to 60 mg; nabilone, in an amountof from 0.5 mg to 6 mg; aprepitant, in an amount of from 20 mg to 750mg; netupitant, in an amount of from 150 mg to 1800 mg; rolapitant, inan amount of from 30 mg to 360 mg; and casopitant, in an amount of from25 mg to 300 mg.

The Component (a/c) of the combination according to this ninthembodiment may be the brand memantine/donepezil fixed-dose combinationcomprising 7 mg-memantine/10 mg-donepezil (Namzaric® 7 mg/10 mg), whichmay be used in multiple unit forms per each administration, when 20 mg,30 mg or 40 mg of donepezil are required.

The Component (b/d) of this ninth embodiment is exhaustively illustratedin WO 2014/039627 (see also US 2015/0231122), the disclosures of whichare incorporated herein in their entirety by reference, the disclosureof which is incorporated herein in its entirety for reference.

According to a preferred aspect of this ninth embodiment, the Component(b/d) is a pharmaceutical composition comprising (b) a naAEA selectedfrom the group consisting of granisetron hydrochloride in an amount (ingranisetron) of from 1 mg to 3 mg, ondansetron hydrochloride dihydratein an amount (in ondansetron) of from 4 mg to 24 mg, domperidone in anamount of from 10 mg to 30 mg; metoclopramide monohydrochloridemonohydrate in an amount (in metoclopramide) of from 10 mg to 30 mg;aprepitant, in an amount of from 40 mg to 375 mg; and (d) solifenacinsuccinate in an amount of from 10 mg to 30 mg, advantageously from 15 mgto 25 mg, preferably of 15 mg, in admixture with a pharmaceuticalcarrier.

According to a tenth embodiment, the invention provides a pharmaceuticalcombination comprising

-   (a/d) a fixed-dose combination essentially consisting of a    pharmaceutical composition in dosage unit form comprising    -   (a) a NMDA-antagonist selected from the group consisting of        memantine or a pharmaceutically acceptable salt thereof, in        amount that is equivalent to from 5 mg to 30 mg of memantine        hydrochloride; and    -   (d) a nsPAChA selected from the group consisting of solifenacin        and pharmaceutically acceptable salts thereof, in an amount that        is equivalent to from 10 mg to 30 mg of solifenacin succinate;    -   in admixture with a pharmaceutical carrier or vehicle; and-   (b/c) a fixed-dose combination essentially consisting of a    pharmaceutical composition in dosage unit form comprising    -   (b) a naAEA; and    -   (c) a ChEI selected from the group consisting of donepezil and        pharmaceutically acceptable salts thereof, in an amount that is        equivalent to from 10 mg to 92 mg, preferably from 20 mg to 92        mg, normally from 10 mg to 70 mg, preferably from 20 mg to 70 mg        of donepezil hydrochloride,    -   in admixture with a pharmaceutical carrier or vehicle.

An advantageous aspect of this tenth embodiment provides a combinationessentially consisting of

-   (a/d) a fixed-dose combination essentially consisting of a    pharmaceutical composition in dosage unit form comprising    -   (a) memantine or a pharmaceutically acceptable salt thereof, in        amount that is equivalent to from 7 mg to 28 mg of memantine        hydrochloride; and    -   (d) solifenacin or a pharmaceutically acceptable salt thereof,        in an amount that is equivalent to from 10 mg to 30 mg,        advantageously from 15 mg to 25 mg, preferably 15 mg of        solifenacin succinate,    -   in admixture with a pharmaceutical carrier or vehicle; and-   (b/c) a fixed-dose combination essentially consisting of a    pharmaceutical composition in dosage unit form comprising    -   (b) a pharmaceutical composition in dosage unit form comprising        a naAEA selected from the group consisting of alosetron and        pharmaceutically acceptable salts and solvates thereof, in        particular the hydrochloride, in an amount (in alosetron) of        from 0.25 mg to 6 mg; azasetron and pharmaceutically acceptable        salts and solvates thereof, in particular the hydrochloride, in        an amount (in azasetron) of from 5 mg to 60 mg; dolasetron and        pharmaceutically acceptable salts and solvates thereof, in        particular the mesylate, in an amount (in dolasetron) of from 25        mg to 600 mg; granisetron and pharmaceutically acceptable salts        and solvates thereof, in particular the hydrochloride, in an        amount (in granisetron) of from 0.5 mg to 6 mg; ondansetron and        pharmaceutically acceptable salts and solvates thereof, in        particular the hydrochloride dihydrate, in an amount (in        ondansetron) of from 2 mg to 64 mg; palonosetron and        pharmaceutically acceptable salts and solvated thereof, in        particular its hydrochloride, in an amount (in palonosetron) of        from 0.25 mg to 3 mg; ramosetron and pharmaceutically acceptable        salts and solvates thereof, in particular its hydrochloride, in        an amount (in ramosetron) of from 0.0125 mg to 0.3 mg;        tropisetron and pharmaceutically acceptable salts and solvates        thereof, in particular the hydrochloride, in an amount of from        2.5 mg to 30 mg; domperidone and pharmaceutically acceptable        salts and solvates thereof, in an amount (in domperidone) of        from 5 mg to 60 mg; haloperidol, in an amount of from 0.5 mg to        60 mg; chlorpromazine and pharmaceutically acceptable salts and        solvates thereof, in particular the hydrochloride, in an amount        (in chlorpromazine) of from 12.5 mg to 600 mg; prochlorperazine        and pharmaceutically acceptable salts and solvates thereof, in        particular the dimaleate, in an amount (in prochlorperazine) of        from 2.5 mg to 30 mg; metoclopramide and pharmaceutically        acceptable salts and solvates thereof, in particular the        monohydrochloride monohydrate, in an amount (in metoclopramide)        of from 5 mg to 60 mg; bromopride and pharmaceutically        acceptable salts and solvates, in particular the        monohydrochloride and the dihydrochloride monohydrate, in an        amount (in bromopride) of from 5 mg to 60 mg; clebopride and        pharmaceutically acceptable salts and solvates thereof, in        particular the hydrogen malate and the hydrochloride        monohydrate, in an amount (in clebopride) of from 0.25 mg to 3        mg; levosulpiride, in an amount of from 12.5 mg to 600 mg;        alizapride and pharmaceutically acceptable salts thereof, in        particular the hydrochloride, in an amount (in alizapride) of        from 25 mg to 300 mg; trimethobenzamide and pharmaceutically        acceptable salts thereof such as the monohydrochloride, in an        amount (in trimethobenzamide) of from 50 mg to 600 mg; meclizine        (also called meclozine) and pharmaceutically acceptable salts        and solvates thereof, in an amount (in meclizine) of from 6.25        mg to 300 mg; promethazine and pharmaceutically acceptable salts        and solvates thereof, in particular the hydrochloride, in an        amount (in promethazine) of from 12.5 mg to 150 mg; dronabinol        in an amount of from 1.25 mg to 60 mg; nabilone, in an amount of        from 0.5 mg to 6 mg; aprepitant, in an amount of from 20 mg to        750 mg; netupitant, in an amount of from 150 mg to 1800 mg;        rolapitant, in an amount of from 30 mg to 360 mg; and        casopitant, in an amount of from 25 mg to 300 mg, in admixture        with a pharmaceutical carrier or vehicle; and    -   (c) donepezil or a pharmaceutically acceptable salts thereof, in        an amount that is equivalent to from 10 mg to 92 mg, preferably        from 20 mg to 92 mg, normally from 10 mg to 70 mg, preferably        from 20 mg to 70 mg of donepezil hydrochloride, in a        pharmaceutical composition in admixture with a pharmaceutical        carrier or vehicle.

Preferably, in the Component ((b/c) fixed-dose combination theNMDA-antagonist Component (a) is memantine hydrochloride and the naAEAComponent (b) is selected from the group consisting of alosetronhydrochloride, in an amount (in alosetron) of from 0.25 mg to 6 mg;azasetron hydrochloride, in an amount (in azasetron) of from 5 mg to 60mg; dolasetron mesylate, in an amount (in dolasetron) of from 25 mg to600 mg; granisetron hydrochloride, in an amount (in granisetron) of from0.5 mg to 6 mg; ondansetron hydrochloride dihydrate, in an amount (inondansetron) of from 2 mg to 64 mg; palonosetron hydrochloride, in anamount (in palonosetron) of from 0.25 mg to 3 mg; ramosetronhydrochloride, in an amount (in ramosetron) of from 0.0125 mg to 0.3 mg,tropisetron hydrochloride, in an amount (in tropisetron) of from 2.5 mgto 30 mg; domperidone and pharmaceutically acceptable salts and solvatesthereof, in an amount (in domperidone) of from 5 mg to 60 mg;haloperidol, in an amount of from 0.5 mg to 60 mg; chlorpromazinehydrochloride, in an amount (in chlorpromazine) of from 12.5 mg to 600mg; prochlorperazine dimaleate, in an amount (in prochlorperazine) offrom 2.5 mg to 30 mg; metoclopramide monohydrochloride monohydrate, inan amount (in metoclopramide) of from 5 mg to 60 mg; bromopridemonohydrochloride or dihydrochloride monohydrate, in an amount (inbromopride) of from 5 mg to 60 mg; clebopride hydrogen malate orhydrochloride monohydrate, in an amount (in clebopride) of from 0.25 mgto 3 mg; levosulpiride, in an amount of from 12.5 mg to 600 mg;alizapride hydrochloride, in an amount (in alizapride) of from 25 mg to300 mg; trimethobenzamide monohydrochloride, in an amount (intrimethobenzamide) of from 50 mg to 600 mg; meclizine (also calledmeclozine) and pharmaceutically acceptable salts and solvates thereof,in an amount (in meclizine) of from 6.25 mg to 300 mg; promethazinehydrochloride, in an amount (in promethazine) of from 12.5 mg to 150 mg;dronabinol in an amount of from 1.25 mg to 60 mg; nabilone, in an amountof from 0.5 mg to 6 mg; aprepitant, in an amount of from 20 mg to 750mg; netupitant, in an amount of from 150 mg to 1800 mg; rolapitant, inan amount of from 30 mg to 360 mg; and casopitant, in an amount of from25 mg to 300 mg.

The Component (c/d), consisting of a pharmaceutical compositioncomprising the ChEI donepezil and the nsPAChA solifenacin, isillustrated in the aforementioned WO 2009/120277 (see also U.S. Pat. No.9,044,472), the disclosures of which are incorporated herein in theirentirety by reference. According to a third advantageous aspect of thistenth embodiment, said Component (c/d) is a pharmaceutically compositionin dosage unit form comprising solifenacin succinate, in an amount offrom 10 mg to 30 mg and donepezil hydrochloride, in an amount of from 10mg to 92 mg, preferably from 20 mg to 92 mg, normally from 10 mg to 70mg, preferably from 20 mg to 70 mg, in admixture with a pharmaceuticalcarrier or vehicle.

According to an eleventh embodiment, the invention provides apharmaceutical combination comprising or essentially consisting of

-   (a) a pharmaceutical composition in dosage unit form comprising    memantine or a pharmaceutically acceptable salt thereof, in an    amount corresponding to from 5 mg to 30 mg of memantine    hydrochloride; and-   (b/c/d) a fixed-dose combination consisting of a pharmaceutical    composition in dosage unit form comprising    -   (b) a naAEA;    -   (c) donepezil or a pharmaceutically acceptable salt thereof, in        an amount that is equivalent to from 10 mg to 92 mg, preferably        from 20 mg to 92 mg, normally from 10 mg to 70 mg, preferably        from 20 mg to 70 mg of donepezil hydrochloride; and    -   (d) solifenacin or a pharmaceutically acceptable salt thereof,        in an amount that is equivalent to from 10 mg to 30 mg,        advantageously from 15 mg to 25 mg, preferably of 15 mg of        solifenacin succinate,    -   in admixture with a pharmaceutical carrier or vehicle.

An advantageous aspect of this eleventh embodiment of the presentinvention provides the above (a)-(b/c/d) combination, wherein

-   -   said Component (a) is a pharmaceutical composition comprising        memantine hydrochloride in an amount of from 7 mg to 28 mg in a        IR- or ER-formulation; and    -   said Component (b/c/d) is a pharmaceutical composition        comprising

-   (b) a naAEA selected from the group consisting of alosetron    hydrochloride, in an amount (in alosetron) of from 0.25 mg to 6 mg;    azasetron hydrochloride, in an amount (in azasetron) of from 5 mg to    60 mg; dolasetron mesylate, in an amount (in dolasetron) of from 25    mg to 600 mg; granisetron hydrochloride, in an amount (in    granisetron) of from 0.5 mg to 6 mg; ondansetron hydrochloride    dihydrate, in an amount (in ondansetron) of from 2 mg to 64 mg;    palonosetron hydrochloride, in an amount (in palonosetron) of from    0.25 mg to 3 mg; ramosetron hydrochloride, in an amount (in    ramosetron) of from 0.0125 mg to 0.3 mg; tropisetron hydrochloride,    in an amount of from 2.5 mg to 30 mg; domperidone, in an amount of    from 5 mg to 60 mg; haloperidol, in an amount of from 0.5 mg to 60    mg; chlorpromazine hydrochloride, in an amount (in chlorpromazine)    of from 12.5 mg to 600 mg; prochlorperazine dimaleate, in an amount    (in prochlorperazine) of from 2.5 mg to 30 mg; metoclopramide    monohydrochloride monohydrate, in an amount (in metoclopramide) of    from 5 mg to 60 mg; bromopride monohydrochloride or bromopride    dihydrochloride monohydrate, in an amount (in bromopride) of from 5    mg to 60 mg; clebopride hydrogen malate or clebopride hydrochloride    monohydrate, in an amount (in clebopride) of from 0.25 mg to 3 mg;    levosulpiride, in an amount of from 12.5 mg to 600 mg; alizapride    hydrochloride, in an amount (in alizapride) of from 25 mg to 300 mg;    trimethobenzamide monohydrochloride, in an amount (in    trimethobenzamide) of from 50 mg to 600 mg; meclizine, in an amount    of from 6.25 mg to 300 mg; promethazine hydrochloride, in an amount    (in promethazine) of from 12.5 mg to 150 mg; dronabinol in an amount    of from 1.25 mg to 60 mg; nabilone, in an amount of from 0.5 mg to 6    mg; aprepitant, in an amount of from 20 mg to 750 mg; netupitant, in    an amount of from 150 mg to 1800 mg; rolapitant, in an amount of    from 30 mg to 360 mg; and casopitant, in an amount of from 25 mg to    300 mg;

-   (c) donepezil hydrochloride in an amount of from 10 mg to 92 mg,    preferably from 20 mg to 92 mg, normally from 10 mg to 70 mg,    preferably from 20 mg to 70 mg; and

-   (d) solifenacin succinate in an amount of from 10 mg to 30 mg,    advantageously from 15 mg to 25 mg. preferably of 15 mg,    in admixture with a pharmaceutical carrier or vehicle.

A second advantageous aspect of this eleventh embodiment of the presentinvention provides the above (a)-(b/c/d) combination, wherein saidComponent (a) is memantine hydrochloride in a pharmaceutical compositioncomprising memantine or a pharmaceutically acceptable salt thereof, inan amount of from 7 mg to 28 mg in a ER-formulation, such as theER-capsules of the brand drug known as Namenda® XR.

According to a twelfth embodiment, the invention provides apharmaceutical combination comprising or essentially consisting of

-   (b) a pharmaceutical composition in dosage unit form comprising a    naAEA; and-   (a/c/d) a fixed-dose combination consisting of a pharmaceutical    composition in dosage unit form comprising    -   (a) memantine or a pharmaceutically acceptable salt thereof, in        an amount corresponding to from 5 mg to 30 mg of memantine        hydrochloride;    -   (c) donepezil or a pharmaceutically acceptable salt thereof, in        an amount that is equivalent to from 10 mg to 92 mg, preferably        from 20 mg to 92 mg, normally from 10 mg to 70 mg, preferably        from 20 mg to 70 mg of donepezil hydrochloride; and    -   (d) solifenacin or a pharmaceutically acceptable salt thereof,        in an amount that is equivalent to from 10 mg to 30 mg,        advantageously from 15 mg to 25 mg, preferably of 15 mg of        solifenacin succinate,    -   in admixture with a pharmaceutical carrier or vehicle.

A first aspect of this twelfth embodiment of the present inventionprovides the above (b)-(a/c/d) combination, wherein

-   -   said Component (b) is a naAEA selected from the group consisting        of alosetron and pharmaceutically acceptable salts and solvates        thereof, in particular the hydrochloride, in an amount (in        alosetron) of from 0.25 mg to 6 mg; azasetron and        pharmaceutically acceptable salts and solvates thereof, in        particular the hydrochloride, in an amount (in azasetron) of        from 5 mg to 60 mg; dolasetron and pharmaceutically acceptable        salts and solvates thereof, in particular the mesylate, in an        amount (in dolasetron) of from 25 mg to 600 mg; granisetron and        pharmaceutically acceptable salts and solvates thereof, in        particular the hydrochloride, in an amount (in granisetron) of        from 0.5 mg to 6 mg; ondansetron and pharmaceutically acceptable        salts and solvates thereof, in particular the hydrochloride        dihydrate, in an amount (in ondansetron) of from 2 mg to 64 mg;        palonosetron and pharmaceutically acceptable salts and solvated        thereof, in particular its hydrochloride, in an amount (in        palonosetron) of from 0.25 mg to 3 mg; ramosetron and        pharmaceutically acceptable salts and solvates thereof, in        particular its hydrochloride, in an amount (in ramosetron) of        from 0.0125 mg to 0.3 mg; tropisetron and pharmaceutically        acceptable salts and solvates thereof, in particular the        hydrochloride, in an amount of from 2.5 mg to 30 mg; domperidone        and pharmaceutically acceptable salts and solvates thereof, in        an amount (in domperidone) of from 5 mg to 60 mg; haloperidol,        in an amount of from 0.5 mg to 60 mg; chlorpromazine and        pharmaceutically acceptable salts and solvates thereof, in        particular the hydrochloride, in an amount (in chlorpromazine)        of from 12.5 mg to 600 mg; prochlorperazine and pharmaceutically        acceptable salts and solvates thereof, in particular the        dimaleate, in an amount (in prochlorperazine) of from 2.5 mg to        30 mg; metoclopramide and pharmaceutically acceptable salts and        solvates thereof, in particular the monohydrochloride        monohydrate, in an amount (in metoclopramide) of from 5 mg to 60        mg; bromopride and pharmaceutically acceptable salts and        solvates, in particular the monohydrochloride and the        dihydrochloride monohydrate, in an amount (in bromopride) of        from 5 mg to 60 mg; clebopride and pharmaceutically acceptable        salts and solvates thereof, in particular the hydrogen malate        and the hydrochloride monohydrate, in an amount (in clebopride)        of from 0.25 mg to 3 mg; levosulpiride, in an amount of from        12.5 mg to 600 mg; alizapride and pharmaceutically acceptable        salts thereof, in particular the hydrochloride, in an amount (in        alizapride) of from 25 mg to 300 mg; trimethobenzamide and        pharmaceutically acceptable salts thereof such as the        monohydrochloride, in an amount (in trimethobenzamide) of from        50 mg to 600 mg; meclizine (also called meclozine) and        pharmaceutically acceptable salts and solvates thereof, in an        amount (in meclizine) of from 6.25 mg to 300 mg; promethazine        and pharmaceutically acceptable salts and solvates thereof, in        particular the hydrochloride, in an amount (in promethazine) of        from 12.5 mg to 150 mg; dronabinol in an amount of from 1.25 mg        to 60 mg; nabilone, in an amount of from 0.5 mg to 6 mg;        aprepitant, in an amount of from 20 mg to 750 mg; netupitant, in        an amount of from 150 mg to 1800 mg; rolapitant, in an amount of        from 30 mg to 360 mg; and casopitant, in an amount of from 25 mg        to 300 mg; and, in the fixed-dose combination Component (a/c/d)    -   said Component (a) is memantine hydrochloride, in an amount of        from 7 mg to 28 mg;    -   said Component (c) is donepezil hydrochloride, in an amount of        from 10 mg to 92 mg, normally from 10 mg to 70 mg; and    -   said Component (d) is solifenacin succinate, in an amount of        from 10 mg to 30 mg, advantageously from 15 mg to 25 mg        preferably of 15 mg.

A second advantageous aspect of this twelfth embodiment of the presentinvention provides the above (b)-(a/b/d) combination essentiallyconsisting of

-   (b) a fixed-dose combination consisting of a pharmaceutical    composition in dosage unit form comprising palonosetron    hydrochloride, in an amount (in palonosetron) of 0.5 mg, and    netupitant, in an amount of 300 mg, in admixture with a    pharmaceutical carrier or vehicle; and-   (a/c/d) a pharmaceutical composition in dosage unit form comprising    -   (a) memantine hydrochloride, in an amount of from 7 mg to 28 mg;    -   (c) donepezil hydrochloride, in an amount of from 10 mg to 92        mg; and    -   (d) solifenacin succinate, in an amount of from 10 mg to 30 mg,        in admixture with a pharmaceutical carrier or vehicle.

The above fixed-dose combination Component (b) may be thepalonosetron/netupitant brand drug known as Akynzeo®.

According to a thirteenth embodiment, the invention provides apharmaceutical combination comprising or essentially consisting of

-   (c) a pharmaceutical composition in dosage unit form comprising    donepezil or a pharmaceutically acceptable salt thereof, in an    amount that is equivalent to from 10 mg to 92 mg, preferably from 20    mg to 92 mg, normally from 10 mg to 70 mg, preferably from 20 mg to    70 mg of donepezil hydrochloride; and;-   (a/b/d) a fixed-dose combination consisting of a pharmaceutical    composition in dosage unit form comprising    -   (a) memantine or a pharmaceutically acceptable salt thereof, in        an amount corresponding to from 5 mg to 30 mg of memantine        hydrochloride;    -   (b) a naAEA; and    -   (d) solifenacin or a pharmaceutically acceptable salt thereof,        in an amount that is equivalent to from 10 mg to 30 mg of        solifenacin succinate,        in admixture with a pharmaceutical carrier or vehicle.

An advantageous aspect of this thirteenth embodiment of the presentinvention provides the above (c)-(a/b/d) combination, wherein

-   -   said Component (c) is a pharmaceutical composition comprising        donepezil hydrochloride in an amount of from 10 mg to 92 mg; and    -   said Component (a/b/d) is a pharmaceutical composition in dosage        unit form comprising    -   (a) memantine hydrochloride in an amount of from 5 mg to 30 mg;    -   (b) a naAEA selected from the group consisting of alosetron        hydrochloride, in an amount (in alosetron) of from 0.25 mg to 6        mg; azasetron hydrochloride, in an amount (in azasetron) of from        5 mg to 60 mg; dolasetron mesylate, in an amount (in dolasetron)        of from 25 mg to 600 mg; granisetron hydrochloride, in an amount        (in granisetron) of from 0.5 mg to 6 mg; ondansetron        hydrochloride dihydrate, in an amount (in ondansetron) of from 2        mg to 64 mg; palonosetron hydrochloride, in an amount (in        palonosetron) of from 0.25 mg to 3 mg; ramosetron hydrochloride,        in an amount (in ramosetron) of from 0.0125 mg to 0.3 mg;        tropisetron hydrochloride, in an amount of from 2.5 mg to 30 mg;        domperidone, in an amount of from 5 mg to 60 mg; haloperidol, in        an amount of from 0.5 mg to 60 mg; chlorpromazine hydrochloride,        in an amount (in chlorpromazine) of from 12.5 mg to 600 mg;        prochlorperazine dimaleate, in an amount (in prochlorperazine)        of from 2.5 mg to 30 mg; metoclopramide monohydrochloride        monohydrate, in an amount (in metoclopramide) of from 5 mg to 60        mg; bromopride monohydrochloride or bromopride dihydrochloride        monohydrate, in an amount (in bromopride) of from 5 mg to 60 mg;        clebopride hydrogen malate or clebopride hydrochloride        monohydrate, in an amount (in clebopride) of from 0.25 mg to 3        mg; levosulpiride, in an amount of from 12.5 mg to 600 mg;        alizapride hydrochloride, in an amount (in alizapride) of from        25 mg to 300 mg; trimethobenzamide monohydrochloride, in an        amount (in trimethobenzamide) of from 50 mg to 600 mg; meclizine        (also called meclozine), in an amount of from 6.25 mg to 300 mg;        promethazine hydrochloride, in an amount (in promethazine) of        from 12.5 mg to 150 mg; dronabinol in an amount of from 1.25 mg        to 60 mg; nabilone, in an amount of from 0.5 mg to 6 mg;        aprepitant, in an amount of from 20 mg to 750 mg; netupitant, in        an amount of from 150 mg to 900 mg; rolapitant, in an amount of        from 30 mg to 360 mg; and casopitant, in an amount of from 25 mg        to 300 mg; and    -   (d) solifenacin succinate in an amount of from 10 mg to 30 mg,        in admixture with a pharmaceutical carrier or vehicle.

According to a fourteenth embodiment, the invention provides apharmaceutical combination comprising or essentially consisting of

-   (d) a pharmaceutical composition in dosage unit form comprising    solifenacin or a pharmaceutically acceptable salt thereof, in an    amount that is equivalent to from 10 mg to 30 mg, advantageously    from 15 mg to 25 mg, preferably of 15 mg of solifenacin succinate,    in admixture with a pharmaceutical carrier or vehicle; and-   (a/b/c) a fixed-dose combination consisting of a pharmaceutical    composition in dosage unit form comprising    -   (a) memantine or a pharmaceutically acceptable salt thereof, in        an amount corresponding to from 5 mg to 30 mg of memantine        hydrochloride;    -   (b) a naAEA; and    -   (c) donepezil or a pharmaceutically acceptable salt thereof, in        an amount that is equivalent to from 10 mg to 92 mg of donepezil        hydrochloride,        -   in admixture with a pharmaceutical carrier or vehicle.

A second advantageous aspect of this fourteenth embodiment of thepresent invention provides the above (d)-(a/b/c) combination, whereinsaid Component (d) in the (a/b/c) fixed-dose combination is a naAEAselected from the group consisting of alosetron and pharmaceuticallyacceptable salts and solvates thereof, in particular the hydrochloride,in an amount (in alosetron) of from 0.25 mg to 6 mg; azasetron andpharmaceutically acceptable salts and solvates thereof, in particularthe hydrochloride, in an amount (in azasetron) of from 5 mg to 60 mg;dolasetron and pharmaceutically acceptable salts and solvates thereof,in particular the mesylate, in an amount (in dolasetron) of from 25 mgto 600 mg; granisetron and pharmaceutically acceptable salts andsolvates thereof, in particular the hydrochloride, in an amount (ingranisetron) of from 0.5 mg to 6 mg; ondansetron and pharmaceuticallyacceptable salts and solvates thereof, in particular the hydrochloridedihydrate, in an amount (in ondansetron) of from 2 mg to 64 mg;palonosetron and pharmaceutically acceptable salts and solvated thereof,in particular its hydrochloride, in an amount (in palonosetron) of from0.25 mg to 3 mg; ramosetron and pharmaceutically acceptable salts andsolvates thereof, in particular its hydrochloride, in an amount (inramosetron) of from 0.0125 mg to 0.3 mg; tropisetron andpharmaceutically acceptable salts and solvates thereof, in particularthe hydrochloride, in an amount of from 2.5 mg to 30 mg; domperidone andpharmaceutically acceptable salts and solvates thereof, in an amount (indomperidone) of from 5 mg to 60 mg; haloperidol, in an amount of from0.5 mg to 60 mg; chlorpromazine and pharmaceutically acceptable saltsand solvates thereof, in particular the hydrochloride, in an amount (inchlorpromazine) of from 12.5 mg to 600 mg; prochlorperazine andpharmaceutically acceptable salts and solvates thereof, in particularthe dimaleate, in an amount (in prochlorperazine) of from 2.5 mg to 30mg; metoclopramide and pharmaceutically acceptable salts and solvatesthereof, in particular the monohydrochloride monohydrate, in an amount(in metoclopramide) of from 5 mg to 60 mg; bromopride andpharmaceutically acceptable salts and solvates, in particular themonohydrochloride and the dihydrochloride monohydrate, in an amount (inbromopride) of from 5 mg to 60 mg; clebopride and pharmaceuticallyacceptable salts and solvates thereof, in particular the hydrogen malateand the hydrochloride monohydrate, in an amount (in clebopride) of from0.25 mg to 3 mg; levosulpiride, in an amount of from 12.5 mg to 600 mg;alizapride and pharmaceutically acceptable salts thereof, in particularthe hydrochloride, in an amount (in alizapride) of from 25 mg to 300 mg;trimethobenzamide and pharmaceutically acceptable salts thereof such asthe monohydrochloride, in an amount (in trimethobenzamide) of from 50 mgto 600 mg; meclizine (also called meclozine) and pharmaceuticallyacceptable salts and solvates thereof, in an amount (in meclizine) offrom 6.25 mg to 300 mg; promethazine and pharmaceutically acceptablesalts and solvates thereof, in particular the hydrochloride, in anamount (in promethazine) of from 12.5 mg to 150 mg; dronabinol in anamount of from 1.25 mg to 60 mg; nabilone, in an amount of from 0.5 mgto 6 mg; aprepitant, in an amount of from 20 mg to 750 mg; netupitant,in an amount of from 150 mg to 1800 mg; rolapitant, in an amount of from30 mg to 360 mg; and casopitant, in an amount of from 25 mg to 300 mg,in admixture with a pharmaceutical carrier or vehicle.

A third advantageous aspect of this fourteenth embodiment, of thepresent invention provides the above (d)-(a/b/c) combination essentiallyconsisting of

-   (d) a pharmaceutical composition in dosage unit form comprising    solifenacin succinate, in an amount of from 10 mg to 30 mg,    advantageously from 15 mg to 25 mg, preferably of 15 mg, in    admixture with a pharmaceutical carrier or vehicle; and-   (a/b/c) a fixed-dose combination consisting of a pharmaceutical    composition in dosage unit form comprising    -   (a) memantine hydrochloride, in an amount of from 5 mg to 30 mg;    -   (b) a naAEA selected from the group consisting of alosetron        hydrochloride, in an amount (in alosetron) of from 0.25 mg to 6        mg; azasetron hydrochloride, in an amount (in azasetron) of from        5 mg to 60 mg; dolasetron mesylate, in an amount (in dolasetron)        of from 25 mg to 600 mg; granisetron hydrochloride, in an amount        (in granisetron) of from 0.5 mg to 6 mg; ondansetron        hydrochloride dihydrate, in an amount (in ondansetron) of from 2        mg to 64 mg; palonosetron hydrochloride, in an amount (in        palonosetron) of from 0.25 mg to 3 mg; ramosetron hydrochloride,        in an amount (in ramosetron) of from 0.0125 mg to 0.3 mg;        tropisetron hydrochloride, in an amount of from 2.5 mg to 30 mg;        domperidone, in an amount of from 5 mg to 60 mg; haloperidol, in        an amount of from 0.5 mg to 60 mg; chlorpromazine hydrochloride,        in an amount (in chlorpromazine) of from 12.5 mg to 600 mg;        prochlorperazine dimaleate, in an amount (in prochlorperazine)        of from 2.5 mg to 30 mg; metoclopramide monohydrochloride        monohydrate, in an amount (in metoclopramide) of from 5 mg to 60        mg; bromopride monohydrochloride or bromopride dihydrochloride        monohydrate, in an amount (in bromopride) of from 5 mg to 60 mg;        clebopride hydrogen malate or clebopride hydrochloride        monohydrate, in an amount (in clebopride) of from 0.25 mg to 3        mg; levosulpiride, in an amount of from 12.5 mg to 600 mg;        alizapride hydrochloride, in an amount (in alizapride) of from        25 mg to 300 mg; trimethobenzamide monohydrochloride, in an        amount (in trimethobenzamide) of from 50 mg to 600 mg; in an        amount of from 6.25 mg to 300 mg; promethazine hydrochloride, in        an amount (in promethazine) of from 12.5 mg to 150 mg;        dronabinol in an amount of from 1.25 mg to 60 mg; nabilone, in        an amount of from 0.5 mg to 6 mg; aprepitant, in an amount of        from 20 mg to 750 mg; netupitant, in an amount of from 150 mg to        1800 mg; rolapitant, in an amount of from 30 mg to 360 mg; and        casopitant, in an amount of from 25 mg to 300 mg; and    -   (c) donepezil hydrochloride, in an amount of from 10 mg to 92        mg, preferably from 20 mg to 92 mg, normally from 10 mg to 70        mg, preferably from 20 mg to 70 mg,        in admixture with a pharmaceutical carrier or vehicle.

A third advantageous aspect of this fourteenth embodiment of the presentinvention provides the above (d)-(a/b/c) combination, wherein saidComponent (a/b/c) essentially consisting of a pharmaceutical compositionin dosage unit form comprising

-   -   (a) memantine hydrochloride, in an amount of from 7 mg to 28 mg;    -   (b) solifenacin succinate, in an amount of from 10 mg to 30 mg;        and    -   (c) donepezil hydrochloride, in an amount of from 10 mg to 92        mg, in admixture with a pharmaceutical carrier or vehicle.

A fourth advantageous aspect of this fourteenth embodiment of thepresent invention provides a (d)-(a/b/c) combination, essentiallyconsisting of

-   -   (d) a pharmaceutical composition in dosage unit form comprising        solifenacin succinate in an amount of from 10 mg to 30 mg,        advantageously from 15 mg to 25 mg, preferably of 15 mg; and

-   (a/b/c) a fixed-dose combination consisting of a pharmaceutical    composition in dosage unit form comprising    -   (a) memantine hydrochloride, in an amount of from 7 mg to 28 mg;    -   (b) aprepitant, in an amount of 40 mg; and    -   (c) donepezil hydrochloride in an amount of from 10 mg to 70 mg,        in admixture with a pharmaceutical carrier or vehicle.

All the aforementioned pharmaceutical compositions, comprising Component(a), Component (b), Component (c), Component (d) or mixtures thereof infixed-dose combinations, are preferably in dosage unit form wherein eachof the active ingredients or mixtures thereof formulated in admixturewith a pharmaceutical carrier.

The pharmaceutical carrier or vehicles and vehicles are those commonlyused for the preparation of compositions for oral, buccal andparenteral, in particular transdermal, administration. Oral forms suchas tablets, soft or hard gelatin capsules, powders or granulates insachets and suitably measured oral solutions or suspensions as well aspatches for transdermal administration are particularly appropriate unitforms.

In said unit form, memantine Component (a), preferably memantinehydrochloride, the naAEA Component (b) donepezil Component (c),especially donepezil hydrochloride, and solifenacin Component (d),especially solifenacin succinate, are mixed, together or separately,according to known technologies, in admixture with a pharmaceuticalcarriers or vehicles, in pharmaceutical compositions according to theabove fourteen embodiments.

Carrier or vehicles for IR tablets include for example starches,cellulose and derivatives thereof; lubricants such as talc, stearic acidor magnesium stearate; diluents such as talc, powdered cellulose,lactose, starches such as maize or corn starch, mannitol, sorbitol;disaggregating agents such as microcrystalline cellulose orcrospovidone; lubricants such as polyethylene glycol or magnesiumstearate; ligands such as methylcellulose, sodiumcarboxymethylcellulose, alginic acid, alginates; sweeteners, such assuchrose, dextrose, mannitol, saccharin; or flavoring agents such asnatural or synthetic oils.

Carriers or vehicles for orally disintegrating tablets include forexample lubricants, aggregating, sweetening, flavoring or disaggregatingagents as well as agents improving the buccal mucosa absorption ofComponent (a) and/or Component (b) and/or Component (d) such assorbitol, mannitol, lactose and cellulose.

Carriers or vehicles for liquid, normally aqueous, suspensions orsolutions include for example antioxidants, such as sodium metabisulfiteor sodium sulfite, thickening agents, such as microcrystallinecellulose, hydroxypropylcellulose, carboxymethylcellulose orpolyvinylpyrrolidone, presevatives such as methyl paraben, ethylparaben, tetra-sodium ethylenediaminotetracetate (sodium edentate),sodium benzoate or an alkaline salt of sorbic acid, as well as flavoringand sweetening agents.

The sweeteners contained in the orally disintegrating tablets and theliquid suspensions or solutions may be natural, optional reduced sugarssuch as sucrose, dextrose, xylitol, mannitol or sorbitol, or syntheticproduct such as sodium saccharine or aspartame.

The flavoring agents are pharmaceutically acceptable flavors and tastesof synthetic and natural oils, the latter extracted from plants, leaves,flowers, fruits and their combinations, such as cinnamon, peppermint,anise and citron leaves, bitter almond, citrus fruits, in particularorange and/or lemon, linden and grapefruit oils. Also chocolate, vanillaor eucalyptus flavor and essences of fruit, in particular apple, pear,peach, strawberry, cherry, apricot, orange, lemon and grapes may beadvantageously used.

According to an embodiment, memantine Component (a) and the naAEAComponent (b) are advantageously combined in a fixed dose combinationfor the simultaneous administration of the two Components, as disclosedherein above as the fifth embodiment and the tenth embodiment of theinvention. This fixed dose combination is for use for the treatment of apatient suffering from of a hypocholinergic disorder such as Alzheimertype dementia, in combination with donepezil Component (c) andsolifenacin Component (d), concurrently or separately administered tosaid patient in need of said treatment.

For oral use, memantine Component (a) and the naAEA Component (b) are incompositions in admixture with pharmaceutical excipients in knownformulations wherein said Components are mixed together or separated,for example in two tablets introduced in a capsule, or in atwo-compartment capsule or in a multilayer (dilayer) tablet wherein thetwo components, for example memantine hydrochloride and ondansetronhydrochloride dihydrate are both in IR form, or wherein the memantinepharmaceutically acceptable salt, especially the hydrochloride, is inER-form, and the naAEA, for example aprepitant, is in IR-form, accordingto the technologies disclosed for example in U.S. Pat. No. 7,303,761 or8,802,143, the disclosures of which are incorporated herein in theirentirety for reference.

Component (a) and Component (b) may also be present in form of one oftheir complexes with a cyclodextrin, for example α-cyclodextrin,β-cyclodextrin, γ-cyclodextrin, 2-hydroxypropyl-β-cyclodextrin ormethyl-β-cyclodextrin.

Component (a) and Component (b) may also be formulated in the form ofmicrocapsules, optionally with one or more carriers or vehicles oradditives.

For oral administration, Component (a) and Component (b), together orseparately, are formulated by mixing the active ingredient withconventional pharmaceutical acceptable carriers or vehicles enablingsaid active ingredients to be formulated in tablets, dragees, orallydisintegrating tablets, capsules, liquid solutions or suspensions,syrups and the like.

The composition according to the present invention may be in form of acapsule containing two tablets as described herein above, one of themcomprising Component (a) and the other comprising Component (b).

The (a/b) fixed-dose combination may also be formulated in tablets inwhich one or both of the two components is in controlled-release form,for example as a dispersion of said component inhydroxypropyl-methyl-cellulose or in a film-coated microgranule.

For example, memantine, preferably memantine hydrochloride in anER-formulation and in an amount of 7 mg or 28 mg, is in the core, andaprepitant, in IR-formulation and in an amount of from 40 mg, is in theouter layer in a bilayer tablet in which, both the core and the outerlayer may be coated with a film.

In said fixed dose combination, the retardant material of said firstlayer and the immediate release carrier second layer are two elementsselected in order to allow respectively an extended (or sustained)release delivery of the memantine pharmaceutically acceptable salts,normally the hydrochloride, and to provide the solifenacinpharmaceutically acceptable salt, normally the succinate, in admixturewith a pharmaceutical carrier for immediate release, for exampleaccording to the technologies described in U.S. Pat. No. 7,303,761 or inU.S. Pat. No. 8,802,143, the disclosures of which are incorporatedherein in their entirety by reference.

Carriers or vehicles and vehicles for ER tablets include retardantmaterials such as is acrylic and methacrylic acid polymers andcopolymers; cellulose derivatives such as hydroxypropylmethylcellulose,hydroxyethylcellulose, hydroxypropylethylcellulose,hydroxypropylcellulose, methylcellulose, ethylcellulose, or sodiumcarboxymethylcellulose; gums; waxes; glycerides or aliphatic alcohols ora mixture thereof.

The memantine/naAEA fixed-dose combination according to the presentinvention may be also formulated in a bi-layer tablet, the first layercontaining for example memantine hydrochloride in an amount of 10 mg inadmixture with a pharmaceutical carrier in IR-formulation and the secondone containing ondansetron hydrochloride dihydrate, in an amount, inondansetron, of 8 mg, in admixture with a pharmaceutical carrier in IRformulation. A third layer, free of active substances, consisting of apharmaceutical carrier could be inserted between said first and saidsecond layer.

An advantageous composition according to this embodiment consists of

-   -   Layer A, comprising from 5 mg to 10 mg of memantine        hydrochloride Component (a) in admixture with a pharmaceutical        carrier or vehicle in a IR formulation; and    -   Layer B, comprising ondansetron hydrochloride dihydrate        Component (b) in an amount (in ondansetron) of from 4 mg to 12        mg, in admixture with a pharmaceutical carrier or vehicle in an        IR-formulation,        said composition being destined to be administered twice per        day, for example in combination with a pharmaceutical        composition comprising solifenacin succinate Component (b) in an        amount of from 10 mg to 30 mg, in admixture with a        pharmaceutical carrier; and with a pharmaceutical composition        comprising donepezil hydrochloride Component (c) in an amount of        from 20 mg to 92 mg, in admixture with a pharmaceutical carrier        or vehicle, both destined to be administered once per day.

According to another embodiment, the invention provides the herein aboveillustrated memantine/naAEA combination comprising

-   (e) memantine or a pharmaceutically acceptable salt thereof; and-   (b) a naAEA,    -   for use for treating a patient suffering from Alzheimer type        dementia in further combination with-   (c) donepezil or a pharmaceutically acceptable salt thereof in an    amount that is equivalent to from 10 mg to 92 mg, preferably from 20    mg to 92 mg, normally from 10 mg to 70 mg, preferably from 20 mg to    70 mg of donepezil hydrochloride, as a single dose; and-   (d) solifenacin or a pharmaceutically acceptable salt thereof.

In particular, according to this embodiment, the invention provides apharmaceutical combination essentially consisting of

-   (a) a pharmaceutical composition in dosage unit form comprising    memantine or a pharmaceutically acceptable salt thereof, in an    amount that is equivalent to from 5 mg to 30 mg of memantine    hydrochloride, in admixture with a pharmaceutical carrier or    vehicle; and-   (b) a pharmaceutical composition in dosage unit form comprising a    naAEA in admixture with a pharmaceutical carrier or vehicle,    for use for the treatment of a patient suffering from Alzheimer type    dementia in further combination with-   (c) a pharmaceutical composition in dosage unit form comprising    donepezil or a pharmaceutically acceptable salt thereof in an amount    that is equivalent to from 20 mg to 161 mg preferably from 20 mg to    92 mg, or from 25 mg to 92 mg, normally from 20 mg to 70 mg or from    25 mg to 70 mg of donepezil hydrochloride, in admixture with a    pharmaceutical carrier or vehicle; and-   (d) a pharmaceutical composition in dosage unit form comprising    solifenacin or a pharmaceutically acceptable salt thereof in an    amount that is equivalent to from 10 mg to 30 mg of solifenacin    succinate, in admixture with a pharmaceutical carrier or vehicle.

Normally, the naAEA active ingredient of Component (b) is selected fromthe group consisting of (b1) 5HT3-antagonists; (b2) DA-antagonists; (b3)HI-antagonists; (b4) cannabinoids; (b5) NK1-antagonists.

Among the above (b1)-(b5) naAEAs, a naAEA selected from the groupconsisting of alosetron and pharmaceutically acceptable salts andsolvates thereof, in particular the hydrochloride, in an amount (inalosetron) of from 0.25 mg to 6 mg; azasetron and pharmaceuticallyacceptable salts and solvates thereof, in particular the hydrochloride,in an amount (in azasetron) of from 5 mg to 60 mg; dolasetron andpharmaceutically acceptable salts and solvates thereof, in particularthe mesylate, in an amount (in dolasetron) of from 25 mg to 600 mg;granisetron and pharmaceutically acceptable salts and solvates thereof,in particular the hydrochloride, in an amount (in granisetron) of from0.5 mg to 6 mg; ondansetron and pharmaceutically acceptable salts andsolvates thereof, in particular the hydrochloride dihydrate, in anamount (in ondansetron) of from 2 mg to 64 mg; palonosetron andpharmaceutically acceptable salts and solvated thereof, in particularits hydrochloride, in an amount (in palonosetron) of from 0.25 mg to 3mg; ramosetron and pharmaceutically acceptable salts and solvatesthereof, in particular its hydrochloride, in an amount (in ramosetron)of from 0.0125 mg to 0.3 mg; tropisetron and pharmaceutically acceptablesalts and solvates thereof, in particular the hydrochloride, in anamount of from 2.5 mg to 30 mg; domperidone and pharmaceuticallyacceptable salts and solvates thereof, in an amount (in domperidone) offrom 5 mg to 60 mg; haloperidol, in an amount of from 0.5 mg to 60 mg;chlorpromazine and pharmaceutically acceptable salts and solvatesthereof, in particular the hydrochloride, in an amount (inchlorpromazine) of from 12.5 mg to 600 mg; prochlorperazine andpharmaceutically acceptable salts and solvates thereof, in particularthe dimaleate, in an amount (in prochlorperazine) of from 2.5 mg to 30mg; metoclopramide and pharmaceutically acceptable salts and solvatesthereof, in particular the monohydrochloride monohydrate, in an amount(in metoclopramide) of from 5 mg to 60 mg; bromopride andpharmaceutically acceptable salts and solvates, in particular themonohydrochloride and the dihydrochloride monohydrate, in an amount (inbromopride) of from 5 mg to 60 mg; clebopride and pharmaceuticallyacceptable salts and solvates thereof, in particular the hydrogen malateand the hydrochloride monohydrate, in an amount (in clebopride) of from0.25 mg to 3 mg; levosulpiride, in an amount of from 12.5 mg to 600 mg;alizapride and pharmaceutically acceptable salts thereof, in particularthe hydrochloride, in an amount (in alizapride) of from 25 mg to 300 mg;trimethobenzamide and pharmaceutically acceptable salts thereof such asthe monohydrochloride, in an amount (in trimethobenzamide) of from 50 mgto 600 mg; meclizine (also called meclozine) and pharmaceuticallyacceptable salts and solvates thereof, in an amount (in meclizine) offrom 6.25 mg to 300 mg; promethazine and pharmaceutically acceptablesalts and solvates thereof, in particular the hydrochloride, in anamount (in promethazine) of from 12.5 mg to 150 mg; dronabinol in anamount of from 1.25 mg to 60 mg; nabilone, in an amount of from 0.5 mgto 6 mg; aprepitant, in an amount of from 20 mg to 750 mg; netupitant,in an amount of from 150 mg to 1800 mg; rolapitant, in an amount of from30 mg to 360 mg; and casopitant, in an amount of from 25 mg to 300 mg isparticularly advantageous.

According to a preferred embodiment, memantine or a pharmaceuticallyacceptable salt thereof and the naAEA are in a fixed-dose combination asillustrated herein above, Said fixed-dose (a/b) combination essentiallyconsists of a pharmaceutical composition, preferably in dosage unitform, comprising said memantine or pharmaceutically acceptable saltthereof, in an amount that is equivalent to from 5 mg to 30 mg; and saidnaAEA is selected from the group consisting of (b1) 5HT3-antagonists;(b2) DA-antagonists; (b3) H1-antagonists; (b4) cannabinoids; (b5)NK1-antagonists.

Among the above (b1)-(b5) naAEA, a naAEA selected from the groupconsisting of alosetron and pharmaceutically acceptable salts andsolvates thereof, in particular the hydrochloride, in an amount (inalosetron) of from 0.25 mg to 6 mg; azasetron and pharmaceuticallyacceptable salts and solvates thereof, in particular the hydrochloride,in an amount (in azasetron) of from 5 mg to 60 mg; dolasetron andpharmaceutically acceptable salts and solvates thereof, in particularthe mesylate, in an amount (in dolasetron) of from 25 mg to 600 mg;granisetron and pharmaceutically acceptable salts and solvates thereof,in particular the hydrochloride, in an amount (in granisetron) of from0.5 mg to 6 mg; ondansetron and pharmaceutically acceptable salts andsolvates thereof, in particular the hydrochloride dihydrate, in anamount (in ondansetron) of from 2 mg to 64 mg; palonosetron andpharmaceutically acceptable salts and solvated thereof, in particularits hydrochloride, in an amount (in palonosetron) of from 0.25 mg to 3mg; ramosetron and pharmaceutically acceptable salts and solvatesthereof, in particular its hydrochloride, in an amount (in ramosetron)of from 0.0125 mg to 0.3 mg; tropisetron and pharmaceutically acceptablesalts and solvates thereof, in particular the hydrochloride, in anamount of from 2.5 mg to 30 mg; domperidone and pharmaceuticallyacceptable salts and solvates thereof, in an amount (in domperidone) offrom 5 mg to 60 mg; haloperidol, in an amount of from 0.5 mg to 60 mg;chlorpromazine and pharmaceutically acceptable salts and solvatesthereof, in particular the hydrochloride, in an amount (inchlorpromazine) of from 12.5 mg to 600 mg; prochlorperazine andpharmaceutically acceptable salts and solvates thereof, in particularthe dimaleate, in an amount (in prochlorperazine) of from 2.5 mg to 30mg; metoclopramide and pharmaceutically acceptable salts and solvatesthereof, in particular the monohydrochloride monohydrate, in an amount(in metoclopramide) of from 5 mg to 60 mg; bromopride andpharmaceutically acceptable salts and solvates, in particular themonohydrochloride and the dihydrochloride monohydrate, in an amount (inbromopride) of from 5 mg to 60 mg; clebopride and pharmaceuticallyacceptable salts and solvates thereof, in particular the hydrogen malateand the hydrochloride monohydrate, in an amount (in clebopride) of from0.25 mg to 3 mg; levosulpiride, in an amount of from 12.5 mg to 600 mg;alizapride and pharmaceutically acceptable salts thereof, in particularthe hydrochloride, in an amount (in alizapride) of from 25 mg to 300 mg;trimethobenzamide and pharmaceutically acceptable salts thereof such asthe monohydrochloride, in an amount (in trimethobenzamide) of from 50 mgto 600 mg; meclizine (also called meclozine) and pharmaceuticallyacceptable salts and solvates thereof, in an amount (in meclizine) offrom 6.25 mg to 300 mg; promethazine and pharmaceutically acceptablesalts and solvates thereof, in particular the hydrochloride, in anamount (in promethazine) of from 12.5 mg to 150 mg; dronabinol in anamount of from 1.25 mg to 60 mg; nabilone, in an amount of from 0.5 mgto 6 mg; aprepitant, in an amount of from 20 mg to 750 mg; netupitant,in an amount of from 150 mg to 1800 mg; rolapitant, in an amount of from30 mg to 360 mg; and casopitant, in an amount of from 25 mg to 300 mg.

This fixed-dose combination is destined to the treatment of a patientsuffering from Alzheimer type dementia in further combination withdonepezil Component (c) and solifenacin Component (d).

Preferably, donepezil hydrochloride and solifenacin succinate areformulated in a new composition comprising said active ingredients inadmixture with a pharmaceutical carrier. Thus, the invention alsoprovides a solifenacin/donepezil fixed-dose combination consisting of apharmaceutical composition in dosage unit form, comprising from 10 mg to30 mg, preferably 15 mg, of solifenacin succinate and from 10 mg to 92mg, normally from 10 mg to 70 mg, preferably from 20 mg to 70 mg, ofdonepezil hydrochloride, in admixture with a pharmaceutical carrier orvehicle Specific donepezil/solifenacin compositions comprise 15 mg ofsolifenacin succinate and donepezil hydrochloride in an amount of from10 mg to 50 mg, preferably of 10 mg, 15 mg, 20 mg, 25 mg, 30 mg 35 mg or40 mg wherein said solifenacin succinate and donepezil hydrochloride donot interact each other.

In particular the pharmaceutical carrier comprises a diluent such astalc, powdered cellulose, lactose; a disaggregating agents such asmicrocrystalline cellulose, crospovidone or a starch, for example maizeor corn starch; a lubricant such as magnesium or calcium stearate; and abinder, such as methyl cellulose, ethyl cellulose or hydroxypropylmethyl cellulose.

Preferably, the pharmaceutical unit form comprising the preferredcomposition according to the present invention is a coated tabletcontaining donepezil hydrochloride, in an amount of from 10 mg to 50 mg,preferably from 10 mg to 40 mg, and solifenacin succinate, in an amountof 15 mg, as active ingredients, in the core, in admixture with apharmaceutical carrier as defined above.

In particular, in the solifenacin/donepezil fixed dose combinationessentially consists of solifenacin succinate, in an amount of from 5.5%to 0.6.5%, donepezil hydrochloride, in an amount of from 4% to 20%; adiluent, in a amount of from 60% to 82%, a disaggregating agent, in aamount of from 6.8% to 7.5%; and a binder, in an amount of from 1.9% to2.5% the total weight of the core. The coating normally is anon-enteric, fast-dissolving layer that covers the core according toknown technologies. Normally, it is constituted by a cellulosederivative such as methyl hydroxyethyl cellulose or hydroxypropyl methylcellulose, a glycerol ester such as diacetin or triacetin and a pigmentsuch as titanium dioxide.

The Kits

The present invention also provides a kit or package containing acombination as described herein, accompanied by instructions for use. Inparticular, a kit of the present invention is a kit comprising acombination of medicaments for the treatment of Alzheimer type dementia.

According to the present invention the kit allows for the maximalfunctional capacity and safety during the treatment of a patient with acombination wherein the components may be administered concurrently orsequentially.

Memantine Component (a), the naAEA Component (b), donepezil Component(c) and solifenacin Component (d) may be present in the kit all in IRform or Component (a) is in ER form and the Components (b), (c) and (d)are each in IR form, each in admixture with a pharmaceutical carrier ina pharmaceutical composition formulated as illustrated herein above,according to known technologies.

Memantine Component (a), solifenacin Component (b) and donepezilComponent (c) may be present in the kit all in IR form or Component (a)is in ER form and at the Components (b) and (c) are each in IR form,each in admixture with a pharmaceutical carrier in a pharmaceuticalcomposition formulated as illustrated herein above, according to knowntechnologies.

The pharmaceutical compositions may be packaged in any manner suitablefor administration to a patient suffering from a hypocholinergicdisorder of the CNS such as Alzheimer type dementia, Lewy body diseasedementia or Parkinson's disease dementia, and the packaging ismanufactured according to known technologies and completed withinstructions for use clearly showing to the patient or to the caregiverhow to take each of the units forms to be administered.

More particularly, according to a first embodiment, the kit of thepresent invention comprises

-   (a) a pharmaceutical composition in ER dosage unit form comprising    or consisting essentially of a therapeutically effective amount of    memantine or a pharmaceutically acceptable salt thereof, preferably    its hydrochloride, in admixture with a pharmaceutical carrier or    vehicle;-   (b) a pharmaceutical composition in dosage unit form comprising or    consisting essentially of a therapeutically effective amount of a    naAEA, in admixture with a pharmaceutical carrier or vehicle;-   (c) a pharmaceutical composition in IR dosage unit form comprising    or consisting essentially of a therapeutically effective amount of    donepezil or a pharmaceutically acceptable salt thereof, in    admixture with a pharmaceutical carrier or vehicle; and-   (d) a pharmaceutical composition in IR dosage unit form comprising    or consisting essentially of a therapeutically effective amount of    solifenacin or a pharmaceutically acceptable salt thereof, in    admixture with a pharmaceutical carrier or vehicle,    for concurrent, sequential or separate administration.

More particularly, according to a further first embodiment, the kit ofthe present invention comprises

-   (a) a pharmaceutical composition in ER dosage unit form comprising    or consisting essentially of a therapeutically effective amount of    memantine or a pharmaceutically acceptable salt thereof, preferably    its hydrochloride, in admixture with a pharmaceutical carrier or    vehicle;-   (b) a pharmaceutical composition in IR dosage unit form comprising    or consisting essentially of a therapeutically effective amount of    solifenacin or a pharmaceutically acceptable salt thereof, in    admixture with a pharmaceutical carrier or vehicle; and-   (c) a pharmaceutical composition in IR dosage unit form comprising    or consisting essentially of a therapeutically effective amount of    donepezil or a pharmaceutically acceptable salt thereof, in    admixture with a pharmaceutical carrier or vehicle,    for concurrent, sequential or separate administration.

According to a second embodiment, the invention provides a kitcomprising

-   (a) a pharmaceutical composition in dosage unit form comprising or    consisting essentially of memantine or a pharmaceutically acceptable    salt thereof, preferably its hydrochloride, in admixture with a    pharmaceutical carrier or vehicle in an IR or ER form;-   (b) a naAEA; and-   (c/d) a fixed-dose combination that is a pharmaceutical composition    comprising or consisting essentially of    -   (c) donepezil or a pharmaceutically acceptable salt, preferably        its hydrochloride, in IR-form; and    -   (d) solifenacin or a pharmaceutically acceptable salt,        preferably its succinate,    -   in admixture with a pharmaceutical carrier or vehicle.

For example, a kit according to this second embodiment may comprise:

-   (a) a pharmaceutical composition in dosage unit form comprising or    consisting essentially of a memantine pharmaceutically acceptable    salt, preferably the hydrochloride in an amount of from 7 mg to 28    mg in admixture with a pharmaceutical carrier or vehicle in an IR or    ER form, in admixture with a pharmaceutical carrier or vehicle;-   (b) a pharmaceutical composition comprising a naAEA selected from    the group consisting of alosetron and pharmaceutically acceptable    salts and solvates thereof, in particular the hydrochloride, in an    amount (in alosetron) of from 0.25 mg to 6 mg; azasetron and    pharmaceutically acceptable salts and solvates thereof, in    particular the hydrochloride, in an amount (in azasetron) of from 5    mg to 60 mg; dolasetron and pharmaceutically acceptable salts and    solvates thereof, in particular the mesylate, in an amount (in    dolasetron) of from 25 mg to 600 mg; granisetron and    pharmaceutically acceptable salts and solvates thereof, in    particular the hydrochloride, in an amount (in granisetron) of from    0.5 mg to 6 mg; ondansetron and pharmaceutically acceptable salts    and solvates thereof, in particular the hydrochloride dihydrate, in    an amount (in ondansetron) of from 2 mg to 64 mg; palonosetron and    pharmaceutically acceptable salts and solvated thereof, in    particular its hydrochloride, in an amount (in palonosetron) of from    0.25 mg to 3 mg; ramosetron and pharmaceutically acceptable salts    and solvates thereof, in particular its hydrochloride, in an amount    (in ramosetron) of from 0.0125 mg to 0.3 mg; tropisetron and    pharmaceutically acceptable salts and solvates thereof, in    particular the hydrochloride, in an amount of from 2.5 mg to 30 mg;    domperidone and pharmaceutically acceptable salts and solvates    thereof, in an amount (in domperidone) of from 5 mg to 60 mg;    haloperidol, in an amount of from 0.5 mg to 60 mg; chlorpromazine    and pharmaceutically acceptable salts and solvates thereof, in    particular the hydrochloride, in an amount (in chlorpromazine) of    from 12.5 mg to 600 mg; prochlorperazine and pharmaceutically    acceptable salts and solvates thereof, in particular the dimaleate,    in an amount (in prochlorperazine) of from 2.5 mg to 30 mg;    metoclopramide and pharmaceutically acceptable salts and solvates    thereof, in particular the monohydrochloride monohydrate, in an    amount (in metoclopramide) of from 5 mg to 60 mg; bromopride and    pharmaceutically acceptable salts and solvates, in particular the    monohydrochloride and the dihydrochloride monohydrate, in an amount    (in bromopride) of from 5 mg to 60 mg; clebopride and    pharmaceutically acceptable salts and solvates thereof, in    particular the hydrogen malate and the hydrochloride monohydrate, in    an amount (in clebopride) of from 0.25 mg to 3 mg; levosulpiride, in    an amount of from 12.5 mg to 600 mg; alizapride and pharmaceutically    acceptable salts thereof, in particular the hydrochloride, in an    amount (in alizapride) of from 25 mg to 300 mg; trimethobenzamide    and pharmaceutically acceptable salts thereof such as the    monohydrochloride, in an amount (in trimethobenzamide) of from 50 mg    to 600 mg; meclizine (also called meclozine) and pharmaceutically    acceptable salts and solvates thereof, in an amount (in meclizine)    of from 6.25 mg to 300 mg; promethazine and pharmaceutically    acceptable salts and solvates thereof, in particular the    hydrochloride, in an amount (in promethazine) of from 12.5 mg to 150    mg; dronabinol in an amount of from 1.25 mg to 60 mg; nabilone, in    an amount of from 0.5 mg to 6 mg; aprepitant, in an amount of from    20 mg to 750 mg; netupitant, in an amount of from 150 mg to 1800 mg;    rolapitant, in an amount of from 30 mg to 360 mg; and casopitant, in    an amount of from 25 mg to 300 mg,    in admixture with a pharmaceutical carrier or vehicle; and-   (c/d) a fixed-dose combination that is a pharmaceutical composition    comprising or consisting essentially of    -   (c) donepezil hydrochloride in an amount of from 10 mg to 92 mg,        preferably from 20 mg to 92 mg, normally from 10 mg to 70 mg,        preferably from 20 mg to 70 mg; and    -   (d) solifenacin succinate in an amount of from 10 mg to 30 mg,        advantageously from 15 mg to 25 mg, preferably of 15 mg;        -   in admixture with a pharmaceutical carrier or vehicle in an            IR form.

According to a further second embodiment, the invention provides a kitcomprising

-   (a) a pharmaceutical composition in dosage unit form comprising or    consisting essentially of memantine or a pharmaceutically acceptable    salt thereof, preferably its hydrochloride, in admixture with a    pharmaceutical carrier or vehicle in an IR or ER form; and-   (b/c) a fixed-dose combination that is a pharmaceutical composition    comprising or consisting essentially of    -   (b) solifenacin or a pharmaceutically acceptable salt,        preferably its succinate; and    -   (c) donepezil or a pharmaceutically acceptable salt, preferably        its hydrochloride, in admixture with a pharmaceutical carrier or        vehicle, in IR-form.

This kit has the advantage of allowing an improvement in the treatmentof a patient suffering from Alzheimer type dementia. In fact, in thecase of the prescription of IR-memantine that must be taken twotimes/day, the kit of the present invention allows the administration ofa composition (b/c) comprising solifenacin and donepezil that areadministered once a day, thus rendering the treatment easier for thepatient or for the caregiver.

For example, a kit according to this second embodiment may comprise:

-   (a) a pharmaceutical composition in dosage unit form comprising or    consisting essentially of a memantine pharmaceutically acceptable    salt, preferably the hydrochloride in an amount of from 7 mg to 28    mg in admixture with a pharmaceutical carrier or vehicle in an IR or    ER form,    in admixture with a pharmaceutical carrier or vehicle; and-   (b/c) a fixed-dose combination that is a pharmaceutical composition    comprising or consisting essentially of    -   (b) a solifenacin pharmaceutically acceptable salt, preferably        the succinate thereof in an amount of from 10 mg to 30 mg,        advantageously from 15 mg to 25 mg, preferably of 15 mg; and    -   (c) a donepezil pharmaceutically acceptable salt, preferably the        hydrochloride thereof in an amount of from 10 mg to 92 mg,        preferably from 20 mg to 92 mg, normally from 10 mg to 70 mg,        preferably from 20 mg to 70 mg;        -   in admixture with a pharmaceutical carrier or vehicle in an            IR form.

An advantageous kit of this second embodiment comprises:

-   (a) a pharmaceutical composition in dosage unit form comprising or    consisting essentially of memantine hydrochloride, in an amount of    from 7 mg to 28 mg in admixture with a pharmaceutical carrier or    vehicle in ER form    in admixture with a pharmaceutical carrier; and-   (b/c) a fixed-dose combination that is a pharmaceutical composition    comprising or consisting essentially of    -   (b) solifenacin succinate, in an amount of from 15 mg to 30 mg;        and    -   (c) donepezil hydrochloride, in an amount of from 40 mg to 92        mg, normally from 40 mg to 70 mg,    -   in admixture with a pharmaceutical carrier or vehicle, in        IR-form.

Another advantageous kit of this second embodiment comprises:

-   (a) a pharmaceutical composition in dosage unit form comprising or    consisting essentially of memantine hydrochloride, in an amount of    from 7 mg to 28 mg in admixture with a pharmaceutical carrier or    vehicle in ER form    in admixture with a pharmaceutical carrier;-   (b) a pharmaceutical composition in dosage unit form comprising a    naAEA selected from the group consisting of alosetron hydrochloride,    in an amount (in alosetron) of from 0.25 mg to 6 mg; azasetron    hydrochloride, in an amount (in azasetron) of from 5 mg to 60 mg;    dolasetron mesylate, in an amount (in dolasetron) of from 25 mg to    600 mg; granisetron hydrochloride, in an amount (in granisetron) of    from 0.5 mg to 6 mg; ondansetron hydrochloride dihydrate, in an    amount (in ondansetron) of from 2 mg to 64 mg; palonosetron    hydrochloride, in an amount (in palonosetron) of from 0.25 mg to 3    mg; ramosetron hydrochloride, in an amount (in ramosetron) of from    0.0125 mg to 0.3 mg; tropisetron hydrochloride, in an amount of from    2.5 mg to 30 mg; domperidone, in an amount of from 5 mg to 60 mg;    haloperidol, in an amount of from 0.5 mg to 60 mg; chlorpromazine    hydrochloride, in an amount (in chlorpromazine) of from 12.5 mg to    600 mg; prochlorperazine dimaleate, in an amount (in    prochlorperazine) of from 2.5 mg to 30 mg; metoclopramide    monohydrochloride monohydrate, in an amount (in metoclopramide) of    from 5 mg to 60 mg; bromopride monohydrochloride or bromopride    dihydrochloride monohydrate, in an amount (in bromopride) of from 5    mg to 60 mg; clebopride hydrogen malate or clebopride hydrochloride    monohydrate, in an amount (in clebopride) of from 0.25 mg to 3 mg;    levosulpiride, in an amount of from 12.5 mg to 600 mg; alizapride    hydrochloride, in an amount (in alizapride) of from 25 mg to 300 mg;    trimethobenzamide monohydrochloride, in an amount (in    trimethobenzamide) of from 50 mg to 600 mg; in an amount of from    6.25 mg to 300 mg; promethazine hydrochloride, in an amount (in    promethazine) of from 12.5 mg to 150 mg; dronabinol in an amount of    from 1.25 mg to 60 mg; nabilone, in an amount of from 0.5 mg to 6    mg; aprepitant, in an amount of from 20 mg to 750 mg; netupitant, in    an amount of from 150 mg to 1800 mg; rolapitant, in an amount of    from 30 mg to 360 mg; and casopitant, in an amount of from 25 mg to    300 mg, in admixture with a pharmaceutical carrier or vehicle; and-   (c/d) a fixed-dose combination that is a pharmaceutical composition    comprising or consisting essentially of    -   (c) donepezil hydrochloride, in an amount of from 10 mg to 50        mg, normally from 10 mg to 40 mg; and    -   (d) solifenacin succinate, in an amount of from 15 mg to 30 mg,    -   in admixture with a pharmaceutical carrier or vehicle, in        IR-form.

An advantageous kit of this second embodiment comprises a pharmaceuticalcombination essentially consisting of:

-   (a) a pharmaceutical composition in dosage unit form comprising or    consisting essentially of memantine hydrochloride, in an amount of    from 7 mg to 28 mg in admixture with a pharmaceutical carrier or    vehicle in ER form in admixture with a pharmaceutical carrier; and-   (b/c) a fixed-dose combination that is a pharmaceutical composition    comprising or consisting essentially of    -   (b) solifenacin succinate, in an amount of 15 mg; and    -   (c) donepezil hydrochloride, in an amount of from 10 mg to 50        mg, normally from 10 mg to 40 mg,    -   in admixture with a pharmaceutical carrier or vehicle, in        IR-form.

This kit may contain the combination disclosed as the third embodimentof the above “The Combinations” section.

According to a third embodiment, the invention provides a kit comprising

-   (a/b) a novel fixed-dose combination that is a pharmaceutical    composition in dosage unit form comprising or consisting essentially    of    -   (a) memantine or a pharmaceutically acceptable salt thereof; and    -   (b) solifenacin or a pharmaceutically acceptable salt thereof,        in admixture with a pharmaceutical carrier or vehicle; and    -   (c) a pharmaceutical composition in dosage unit form comprising        or consisting essentially of a nsPAChA in admixture with a        pharmaceutical carrier.

According to a third embodiment, the invention provides a kitcomprising:

-   (a/d) a fixed-dose combination that is a pharmaceutical composition    comprising or consisting essentially of    -   (a) memantine or a pharmaceutically acceptable salt thereof, in        an amount that is equivalent to from 5 mg to 30 mg of memantine        hydrochloride, said salt being preferably the hydrochloride; and    -   (d) solifenacin or a pharmaceutically acceptable salt thereof,        in an amount that is equivalent to from 10 mg to 30 mg of        solifenacin succinate, said salt being preferably the succinate;    -   in admixture with a pharmaceutical carrier or vehicle;-   (b) a pharmaceutical composition in comprising a naAEA selected from    the group consisting of alosetron and pharmaceutically acceptable    salts and solvates thereof, in particular the hydrochloride, in an    amount (in alosetron) of from 0.25 mg to 6 mg; azasetron and    pharmaceutically acceptable salts and solvates thereof, in    particular the hydrochloride, in an amount (in azasetron) of from 5    mg to 60 mg; dolasetron and pharmaceutically acceptable salts and    solvates thereof, in particular the mesylate, in an amount (in    dolasetron) of from 25 mg to 600 mg; granisetron and    pharmaceutically acceptable salts and solvates thereof, in    particular the hydrochloride, in an amount (in granisetron) of from    0.5 mg to 6 mg; ondansetron and pharmaceutically acceptable salts    and solvates thereof, in particular the hydrochloride dihydrate, in    an amount (in ondansetron) of from 2 mg to 64 mg; palonosetron and    pharmaceutically acceptable salts and solvated thereof, in    particular its hydrochloride, in an amount (in palonosetron) of from    0.25 mg to 3 mg; ramosetron and pharmaceutically acceptable salts    and solvates thereof, in particular its hydrochloride, in an amount    (in ramosetron) of from 0.0125 mg to 0.3 mg; tropisetron and    pharmaceutically acceptable salts and solvates thereof, in    particular the hydrochloride, in an amount of from 2.5 mg to 30 mg;    domperidone and pharmaceutically acceptable salts and solvates    thereof, in an amount (in domperidone) of from 5 mg to 60 mg;    haloperidol, in an amount of from 0.5 mg to 60 mg; chlorpromazine    and pharmaceutically acceptable salts and solvates thereof, in    particular the hydrochloride, in an amount (in chlorpromazine) of    from 12.5 mg to 600 mg; prochlorperazine and pharmaceutically    acceptable salts and solvates thereof, in particular the dimaleate,    in an amount (in prochlorperazine) of from 2.5 mg to 30 mg;    metoclopramide and pharmaceutically acceptable salts and solvates    thereof, in particular the monohydrochloride monohydrate, in an    amount (in metoclopramide) of from 5 mg to 60 mg; bromopride and    pharmaceutically acceptable salts and solvates, in particular the    monohydrochloride and the dihydrochloride monohydrate, in an amount    (in bromopride) of from 5 mg to 60 mg; clebopride and    pharmaceutically acceptable salts and solvates thereof, in    particular the hydrogen malate and the hydrochloride monohydrate, in    an amount (in clebopride) of from 0.25 mg to 3 mg; levosulpiride, in    an amount of from 12.5 mg to 600 mg; alizapride and pharmaceutically    acceptable salts thereof, in particular the hydrochloride, in an    amount (in alizapride) of from 25 mg to 300 mg; trimethobenzamide    and pharmaceutically acceptable salts thereof such as the    monohydrochloride, in an amount (in trimethobenzamide) of from 50 mg    to 600 mg; meclizine (also called meclozine) and pharmaceutically    acceptable salts and solvates thereof, in an amount (in meclizine)    of from 6.25 mg to 300 mg; promethazine and pharmaceutically    acceptable salts and solvates thereof, in particular the    hydrochloride, in an amount (in promethazine) of from 12.5 mg to 150    mg; dronabinol in an amount of from 1.25 mg to 60 mg; nabilone, in    an amount of from 0.5 mg to 6 mg; aprepitant, in an amount of from    20 mg to 750 mg; netupitant, in an amount of from 150 mg to 1800 mg;    rolapitant, in an amount of from 30 mg to 360 mg; and casopitant, in    an amount of from 25 mg to 300 mg,    in admixture with a pharmaceutical carrier or vehicle; and-   (c) a pharmaceutical composition in dosage unit form comprising or    consisting essentially of donepezil or a pharmaceutically acceptable    salt thereof, in an amount that is equivalent to from 10 mg to 92    mg, preferably from 20 mg to 92 mg, normally from 10 mg to 70 mg,    preferably from 20 mg to 70 mg of donepezil hydrochloride, said salt    being preferably the hydrochloride, in admixture with a    pharmaceutical carrier or vehicle, in IR-form.

An advantageous kit according to this third embodiment provides a kitcomprising:

-   (a/b) a fixed-dose combination that is a novel pharmaceutical    composition comprising or consisting essentially of    -   (a) memantine or a pharmaceutically acceptable salt thereof, in        an amount that is equivalent to from 5 mg to 30 mg of memantine        hydrochloride, said salt being preferably the hydrochloride; and    -   (b) solifenacin or a pharmaceutically acceptable salt thereof,        in an amount that is equivalent to from 10 mg to 30 mg of        solifenacin succinate, said salt being preferably the succinate;    -   in admixture with a pharmaceutical carrier or vehicle; and-   (c) a pharmaceutical composition in dosage unit form comprising or    consisting essentially of donepezil or a pharmaceutically acceptable    salt thereof, in an amount that is equivalent to from 20 mg to 92 mg    of donepezil hydrochloride, said salt being preferably the    hydrochloride, in admixture with a pharmaceutical carrier or    vehicle, in IR-form.

In a preferred kit according to this third embodiment, the Component(a/b) comprises memantine hydrochloride, in an amount of from 7 mg to 28mg and solifenacin succinate, in an amount of from 15 mg to 30 mg; andThe Component (c) comprises donepezil hydrochloride in an amount of from40 mg to 92 mg, normally from 40 mg to 70 mg.

The fixed-dose combination (a/b) is exhaustively illustrated hereinabove.

In a preferred kit according to this third embodiment, thepharmaceutical composition Component (a/d) comprises memantinehydrochloride, in an amount of from 7 mg to 28 mg and solifenacinsuccinate, in an amount of 15 mg to 30 mg preferably of 15 mg; thepharmaceutical composition Component (b) comprises a naAEA selected fromthe group consisting of ondansetron hydrochloride dihydrate, in anamount (in ondansetron) of from 4 mg to 32 mg, domperidone, in an amountof from 10 mg to 30 mg; metoclopramide monohydrochloride monohydrate, inan amount of from 10 mg to 30 mg and aprepitant, in an amount of 40 mg;and the pharmaceutical composition Component (c) comprises donepezilhydrochloride in an amount of from 10 mg to 70 mg or from 40 mg to 70mg. In said compositions, the active ingredients are in admixture with apharmaceutical carrier or vehicle.

An advantageous kit according to this third embodiment provides a kitcomprising:

-   (a/b) a fixed-dose combination that is a novel pharmaceutical    composition comprising or consisting essentially of    -   (a) memantine or a pharmaceutically acceptable salt thereof, in        an amount that is equivalent to from 5 mg to 30 mg of memantine        hydrochloride, said salt being preferably the hydrochloride; and    -   (b) solifenacin or a pharmaceutically acceptable salt thereof,        in an amount that is equivalent to from 10 mg to 30 mg,        advantageously from 15 mg to 25 mg, of solifenacin succinate,        said salt being preferably the succinate;    -   in admixture with a pharmaceutical carrier or vehicle; and-   (c) a pharmaceutical composition in dosage unit form comprising or    consisting essentially of donepezil or a pharmaceutically acceptable    salt thereof, in an amount that is equivalent to from 10 mg to 92    mg, advantageously from 20 mg to 92 mg of donepezil hydrochloride,    said salt being preferably the hydrochloride, in admixture with a    pharmaceutical carrier or vehicle, in IR-form.

In a preferred kit according to this third embodiment, thepharmaceutical composition Component (a/b) comprises memantinehydrochloride, in an amount of from 7 mg to 28 mg and solifenacinsuccinate, in an amount of from 15 mg to 30 mg, preferably of 15 mg; andthe pharmaceutical composition Component (c) comprises donepezilhydrochloride in an amount of from 10 mg to 92 mg, preferably from 20 mgto 92 mg, normally from 10 mg to 70 mg, preferably from 20 mg to 70 mgor from 40 mg to 70 mg. In said compositions, the active ingredients arein admixture with a pharmaceutical carrier or vehicle.

The fixed-dose combination (a/b) is exhaustively illustrated hereinabove.

According to a fourth embodiment, the invention provides a kitcomprising

-   (a/c) a fixed-dose combination that is a pharmaceutical composition    comprising or consisting essentially of    -   (a) memantine or a pharmaceutically acceptable salt thereof; and    -   (c) donepezil or a pharmaceutically acceptable salt thereof,    -   in admixture with a pharmaceutical carrier or vehicle; and    -   (b) a pharmaceutical composition in dosage unit form comprising        or consisting essentially of solifenacin or a pharmaceutically        acceptable salt thereof in admixture with a pharmaceutical        carrier.

According to a fourth embodiment, the invention provides a kitcomprising

-   (a/c) a fixed-dose combination that is a pharmaceutical composition    comprising or consisting essentially of    -   (a) memantine or a pharmaceutically acceptable salt thereof; and    -   (c) donepezil or a pharmaceutically acceptable salt thereof,    -   in admixture with a pharmaceutical carrier or vehicle; and-   (b) a pharmaceutical composition in comprising a naAEA selected from    the group consisting of alosetron and pharmaceutically acceptable    salts and solvates thereof, in particular the hydrochloride, in an    amount (in alosetron) of from 0.25 mg to 6 mg; azasetron and    pharmaceutically acceptable salts and solvates thereof, in    particular the hydrochloride, in an amount (in azasetron) of from 5    mg to 60 mg; dolasetron and pharmaceutically acceptable salts and    solvates thereof, in particular the mesylate, in an amount (in    dolasetron) of from 25 mg to 600 mg; granisetron and    pharmaceutically acceptable salts and solvates thereof, in    particular the hydrochloride, in an amount (in granisetron) of from    0.5 mg to 6 mg; ondansetron and pharmaceutically acceptable salts    and solvates thereof, in particular the hydrochloride dihydrate, in    an amount (in ondansetron) of from 2 mg to 64 mg; palonosetron and    pharmaceutically acceptable salts and solvated thereof, in    particular its hydrochloride, in an amount (in palonosetron) of from    0.25 mg to 3 mg; ramosetron and pharmaceutically acceptable salts    and solvates thereof, in particular its hydrochloride, in an amount    (in ramosetron) of from 0.0125 mg to 0.3 mg; tropisetron and    pharmaceutically acceptable salts and solvates thereof, in    particular the hydrochloride, in an amount of from 2.5 mg to 30 mg;    domperidone and pharmaceutically acceptable salts and solvates    thereof, in an amount (in domperidone) of from 5 mg to 60 mg;    haloperidol, in an amount of from 0.5 mg to 60 mg; chlorpromazine    and pharmaceutically acceptable salts and solvates thereof, in    particular the hydrochloride, in an amount (in chlorpromazine) of    from 12.5 mg to 600 mg; prochlorperazine and pharmaceutically    acceptable salts and solvates thereof, in particular the dimaleate,    in an amount (in prochlorperazine) of from 2.5 mg to 30 mg;    metoclopramide and pharmaceutically acceptable salts and solvates    thereof, in particular the monohydrochloride monohydrate, in an    amount (in metoclopramide) of from 5 mg to 60 mg; bromopride and    pharmaceutically acceptable salts and solvates, in particular the    monohydrochloride and the dihydrochloride monohydrate, in an amount    (in bromopride) of from 5 mg to 60 mg; clebopride and    pharmaceutically acceptable salts and solvates thereof, in    particular the hydrogen malate and the hydrochloride monohydrate, in    an amount (in clebopride) of from 0.25 mg to 3 mg; levosulpiride, in    an amount of from 12.5 mg to 600 mg; alizapride and pharmaceutically    acceptable salts thereof, in particular the hydrochloride, in an    amount (in alizapride) of from 25 mg to 300 mg; trimethobenzamide    and pharmaceutically acceptable salts thereof such as the    monohydrochloride, in an amount (in trimethobenzamide) of from 50 mg    to 600 mg; meclizine (also called meclozine) and pharmaceutically    acceptable salts and solvates thereof, in an amount (in meclizine)    of from 6.25 mg to 300 mg; promethazine and pharmaceutically    acceptable salts and solvates thereof, in particular the    hydrochloride, in an amount (in promethazine) of from 12.5 mg to 150    mg; dronabinol in an amount of from 1.25 mg to 60 mg; nabilone, in    an amount of from 0.5 mg to 6 mg; aprepitant, in an amount of from    20 mg to 750 mg; netupitant, in an amount of from 150 mg to 1800 mg;    rolapitant, in an amount of from 30 mg to 360 mg; and casopitant, in    an amount of from 25 mg to 300 mg,    in admixture with a pharmaceutical carrier or vehicle; and-   (d) a pharmaceutical composition in dosage unit form comprising or    consisting essentially of solifenacin or a pharmaceutically    acceptable salt thereof in admixture with a pharmaceutical carrier.

This fourth embodiment provides an advantageous kit comprising:

-   (a/c) a fixed-dose combination that is a pharmaceutical composition    comprising or consisting essentially of-   (a/c) a novel fixed-dose combination that is a pharmaceutical    composition comprising or consisting essentially of    -   (a) a memantine or a pharmaceutically acceptable salt thereof,        preferably the hydrochloride thereof in an amount of from 5 mg        to 30 mg; and    -   (c) donepezil or a pharmaceutically acceptable salt thereof,        preferably the hydrochloride thereof in an amount of from 20 mg        to 92 mg, in admixture with a pharmaceutical carrier or vehicle;        and-   (b) a pharmaceutical composition in dosage unit form comprising or    consisting essentially of solifenacin or a pharmaceutically    acceptable salt thereof, preferably the succinate thereof in an    amount of from 10 mg to 30 mg, in admixture with a pharmaceutical    carrier or vehicle.

This fourth embodiment provides an advantageous kit comprising:

-   (a/c) a fixed-dose combination that is a pharmaceutical composition    comprising or consisting essentially of    -   (a) a memantine or a pharmaceutically acceptable salt thereof,        preferably the hydrochloride thereof in an amount of from 5 mg        to 30 mg; and    -   (c) donepezil or a pharmaceutically acceptable salt thereof,        preferably the hydrochloride thereof in an amount of from 10 mg        to 92 mg, preferably from 20 mg to 92 mg, normally from 10 mg to        70 mg, preferably from 20 mg to 70 mg,        in admixture with a pharmaceutical carrier or vehicle;-   (b) a pharmaceutical composition in dosage unit form comprising or    consisting essentially of a naAEA selected from the group consisting    of alosetron and pharmaceutically acceptable salts and solvates    thereof, in particular the hydrochloride, in an amount (in    alosetron) of from 0.25 mg to 6 mg; azasetron and pharmaceutically    acceptable salts and solvates thereof, in particular the    hydrochloride, in an amount (in azasetron) of from 5 mg to 60 mg;    dolasetron and pharmaceutically acceptable salts and solvates    thereof, in particular the mesylate, in an amount (in dolasetron) of    from 25 mg to 600 mg; granisetron and pharmaceutically acceptable    salts and solvates thereof, in particular the hydrochloride, in an    amount (in granisetron) of from 0.5 mg to 6 mg; ondansetron and    pharmaceutically acceptable salts and solvates thereof, in    particular the hydrochloride dihydrate, in an amount (in    ondansetron) of from 2 mg to 64 mg; palonosetron and    pharmaceutically acceptable salts and solvated thereof, in    particular its hydrochloride, in an amount (in palonosetron) of from    0.25 mg to 3 mg; ramosetron and pharmaceutically acceptable salts    and solvates thereof, in particular its hydrochloride, in an amount    (in ramosetron) of from 0.0125 mg to 0.3 mg; tropisetron and    pharmaceutically acceptable salts and solvates thereof, in    particular the hydrochloride, in an amount of from 2.5 mg to 30 mg;    domperidone and pharmaceutically acceptable salts and solvates    thereof, in an amount (in domperidone) of from 5 mg to 60 mg;    haloperidol, in an amount of from 0.5 mg to 60 mg; chlorpromazine    and pharmaceutically acceptable salts and solvates thereof, in    particular the hydrochloride, in an amount (in chlorpromazine) of    from 12.5 mg to 600 mg; prochlorperazine and pharmaceutically    acceptable salts and solvates thereof, in particular the dimaleate,    in an amount (in prochlorperazine) of from 2.5 mg to 30 mg;    metoclopramide and pharmaceutically acceptable salts and solvates    thereof, in particular the monohydrochloride monohydrate, in an    amount (in metoclopramide) of from 5 mg to 60 mg; bromopride and    pharmaceutically acceptable salts and solvates, in particular the    monohydrochloride and the dihydrochloride monohydrate, in an amount    (in bromopride) of from 5 mg to 60 mg; clebopride and    pharmaceutically acceptable salts and solvates thereof, in    particular the hydrogen malate and the hydrochloride monohydrate, in    an amount (in clebopride) of from 0.25 mg to 3 mg; levosulpiride, in    an amount of from 12.5 mg to 600 mg; alizapride and pharmaceutically    acceptable salts thereof, in particular the hydrochloride, in an    amount (in alizapride) of from 25 mg to 300 mg; trimethobenzamide    and pharmaceutically acceptable salts thereof such as the    monohydrochloride, in an amount (in trimethobenzamide) of from 50 mg    to 600 mg; meclizine (also called meclozine) and pharmaceutically    acceptable salts and solvates thereof, in an amount (in meclizine)    of from 6.25 mg to 300 mg; promethazine and pharmaceutically    acceptable salts and solvates thereof, in particular the    hydrochloride, in an amount (in promethazine) of from 12.5 mg to 150    mg; dronabinol in an amount of from 1.25 mg to 60 mg; nabilone, in    an amount of from 0.5 mg to 6 mg; aprepitant, in an amount of from    20 mg to 750 mg; netupitant, in an amount of from 150 mg to 1800 mg;    rolapitant, in an amount of from 30 mg to 360 mg; and casopitant, in    an amount of from 25 mg to 300 mg,    in admixture with a pharmaceutical carrier or vehicle; and-   (d) a pharmaceutical composition in dosage unit form comprising or    consisting essentially of solifenacin or a pharmaceutically    acceptable salt thereof, preferably the succinate thereof in an    amount of from 10 mg to 30 mg, advantageously from 15 mg to 25 mg,    preferably of 15 mg,    in admixture with a pharmaceutical carrier or vehicle.

In a preferred kit according to this fourth embodiment, thepharmaceutical composition Component (a/c) comprises memantinehydrochloride, in an amount of from 7 mg to 28 mg; and donepezilhydrochloride, in an amount of from 10 mg to 70 mg, normally from 40 mgto 70 mg; the pharmaceutical composition Component (b) is a fixed dosecombination consisting of a pharmaceutical composition comprisingnetupitant in an amount of 300 mg and palonosetron hydrochloride in anamount, in palonosetron of 0.5 mg; and the pharmaceutical compositionComponent (d) comprises solifenacin succinate, in an amount of from 10mg to 30 mg, advantageously from 15 mg to 25 mg, preferably of 15 mg. insaid pharmaceutical compositions, the active ingredient are in admixturewith a pharmaceutical carrier or vehicle. In particular, Component (b)may be the brand palonosetron/netupitant fixed-dose combination known asAkynzeo®.

According to a fourth embodiment, the invention provides a kitcomprising

-   (a/c) a fixed-dose combination that is a pharmaceutical composition    comprising or consisting essentially of    -   (a) memantine or a pharmaceutically acceptable salt thereof; and    -   (c) donepezil or a pharmaceutically acceptable salt thereof,    -   in admixture with a pharmaceutical carrier or vehicle; and-   (b) a pharmaceutical composition in dosage unit form comprising or    consisting essentially of solifenacin or a pharmaceutically    acceptable salt thereof in admixture with a pharmaceutical carrier.

This fourth embodiment provides an advantageous kit comprising:

-   (a/c) a fixed-dose combination that is a pharmaceutical composition    comprising or consisting essentially of    -   (a) a memantine or a pharmaceutically acceptable salt thereof,        preferably the hydrochloride thereof in an amount of from 5 mg        to 30 mg; and    -   (c) donepezil or a pharmaceutically acceptable salt thereof,        preferably the hydrochloride thereof in an amount of from 10 mg        to 92 mg, preferably from 20 mg to 92 mg, normally from 10 mg to        70 mg, preferably from 20 mg to 70 mg, advantageously from 20 mg        to 92 mg,    -   in admixture with a pharmaceutical carrier or vehicle; and-   (b) a pharmaceutical composition in dosage unit form comprising or    consisting essentially of solifenacin or a pharmaceutically    acceptable salt thereof, preferably the succinate thereof in an    amount of from 10 mg to 30 mg, advantageously from 15 mg to 25 mg,    preferably of 15 mg,    in admixture with a pharmaceutical carrier or vehicle.

In a preferred kit according to this fourth embodiment, thepharmaceutical composition Component (a/c) comprises memantinehydrochloride, in an amount of from 7 mg to 28 mg; and donepezilhydrochloride, in an amount of from 2040 mg to 70 mg or from 40 mg to 70mg; and the pharmaceutical composition Component (b) comprisessolifenacin succinate, in an amount of from 15 mg to 25 mg.

In a preferred kit according to this embodiment, the Component (a/c)comprises memantine hydrochloride, in an amount of from 7 mg to 28 mg;and donepezil hydrochloride, in an amount of from 40 mg to 92 mg,normally from 40 mg to 70 mg; and the Component (b) is solifenacinsuccinate, in an amount of from 15 mg to 30 mg.

The aforementioned kits may help the physician, the relatives and thecaregiver to render the supply of the medicaments to the patient morecomfortable.

The pathologic conditions treated with the compositions and kits of thepresent invention include, but are not limited to, Alzheimer's disease,Parkinson's disease dementia, Lewy body dementia and other disorders ofhuman cognitive and neurobehavioral function that are treated, in part,by pharmaceuticals intended to augment brain acetylcholine-mediatedneurotransmission.

As set forth above, the fact that the combinations and kits of thepresent invention allow a better response to the memantine therapy ofAlzheimer type dementia in respect to the response obtained withmemantine alone, results from a surprising finding in a limited butindicative clinical investigation in patients with moderate dementia,among whom some ones were under treatment with memantine.

The above combined memantine/solifenacin/donepezil treatment involvesgreater and longer efficacy and less adverse effects by allowing thesafe and tolerable administration of therapeutically effective,high-doses of donepezil. In particular, the treatment with donepezilaccording to the present invention is safe and effective, also incombination with other pharmaceuticals, in treating patients in need ofan acetylcholine esterase inhibition, in particular dementias of theAlzheimer type on a normally once daily basis.

The presence of an antiemetic agent in the combinations of the presentinvention assures a safe administration of high and even very high dosesof donepezil.

The Method

As indicated above, the present invention also proposes a method for thetreatment of Alzheimer type dementia, which comprises treating a patientin need of said treatment with an effective amount of aN-methyl-D-aspartate receptor antagonist selected from the groupconsisting of memantine and pharmaceutical acceptable salts thereof[Component (a)], and with an effective amount of a non-selectiveperipheral anticholinergic agent selected from the group consisting ofsolifenacin and pharmaceutically acceptable salts thereof [Component(b)], in combination with a cholinesterase inhibitor selected from thegroup consisting of donepezil and pharmaceutically acceptable saltsthereof [Component (c)]. Said donepezil or pharmaceutical acceptablesalt is administered at a daily dose that is equivalent to from 10 mg to92 mg, preferably from 20 mg to 92 mg, normally from 10 mg to 70 mg,preferably from 20 mg to 70 mg of donepezil hydrochloride.

Thanks to the solifenacin/memantine synergism, said donepezil amount mayadvantageously be of from 20 mg to 70 mg or from 40 mg to 70 mg, as asingle dose, with substantially improved therapeutic response.

In general, said Component (a) is memantine or a pharmaceuticallyacceptable salt thereof, at a daily dose that is equivalent to from 5 mgto 30 mg of memantine hydrochloride, and said Component (b) issolifenacin or a pharmaceutically acceptable salt thereof, at a dailydose that is equivalent to from 10 mg to 30 mg, advantageously from 15mg to 25 mg, preferably of 15 mg of solifenacin succinate.

Advantageously, said Component (a) is memantine or a pharmaceuticallyacceptable salt thereof, in a pharmaceutical composition comprising saidmemantine or pharmaceutically acceptable salt thereof in an amount thatis equivalent to from 5 mg to 30 mg of memantine hydrochloride, inadmixture with a pharmaceutical carrier or vehicle; said Component (b)is solifenacin or a pharmaceutically acceptable salt thereof, in apharmaceutical composition comprising said solifenacin orpharmaceutically acceptable salt thereof in an amount that is equivalentto from 10 mg to 30 mg, advantageously from 15 mg to 25 mg, preferablyof 15 mg of solifenacin succinate; and said Component (c) is donepezilor a pharmaceutically acceptable salt thereof, in a pharmaceuticalcomposition comprising said donepezil or pharmaceutically acceptablesalt thereof in an amount that is equivalent to 10 mg to 92 mg,preferably from 20 mg to 92 mg, normally from 10 mg to 70 mg, preferablyfrom 20 mg to 70 mg of donepezil hydrochloride. Due to thesolifenacin/memantine synergism, said donepezil amount mayadvantageously be of from 40 mg to 70 mg.

According to an embodiment, said Component (a) is memantinehydrochloride, in a pharmaceutical composition comprising said memantinehydrochloride in an amount of from 7 mg to 28 mg, in admixture with apharmaceutical carrier in an extended-release formulation; and saidComponent (b) is solifenacin succinate, in a pharmaceutical compositioncomprising said solifenacin succinate in an amount of from 10 mg to 30mg, advantageously from 15 mg to 25 mg, preferably of 15 mg, inadmixture with a pharmaceutical carrier or vehicle in animmediate-release formulation.

According to another embodiment, said Component (a) is memantinehydrochloride, in a pharmaceutical composition comprising said memantinehydrochloride in an amount of from 5 mg to 10 mg, in admixture with apharmaceutical carrier in an immediate-release formulation; and saidComponent (b) is solifenacin succinate, in a pharmaceutical compositioncomprising said solifenacin succinate in an amount of from 10 mg to 30mg, advantageously from 15 mg to 25 mg, preferably of 15 mg, inadmixture with a pharmaceutical carrier or vehicle in animmediate-release formulation.

According to another embodiment, said Component (a) is memantinehydrochloride, in a pharmaceutical composition comprising said memantinehydrochloride in an amount of from 5 mg to 10 mg, in admixture with apharmaceutical carrier in an immediate-release formulation; saidComponent (b) is solifenacin succinate, in a pharmaceutical compositioncomprising said solifenacin succinate in an amount of from 10 mg to 30mg, advantageously from 15 mg to 25 mg, preferably of 15 mg, inadmixture with a pharmaceutical carrier or vehicle in an immediaterelease formulation; and said Component (c) is donepezil hydrochloride,in a pharmaceutical composition comprising said donepezil hydrochloride,in an amount of from 10 mg to 70 mg, advantageously from 10 mg to 50 mg,preferably from 10 mg to 40 mg, in admixture with a pharmaceuticalcarrier or vehicle.

According to a preferred embodiment, the method of the present inventionis carried out by using said Component (a) and said Component (b) in afixed-dose combination consisting of a pharmaceutical compositioncomprising memantine or a pharmaceutically acceptable salt thereof[Component (a)], in an amount that is equivalent to from 5 mg to 30 mg,preferably from 7 mg to 28 mg, of memantine hydrochloride, andsolifenacin or a pharmaceutically acceptable salt thereof [Component(b)], in an amount that is equivalent to from 5 mg to 30 mg,advantageously of from 15 mg to 25 mg, preferably of 15 mg, ofsolifenacin succinate,

in admixture with a pharmaceutical carrier or vehicle.

As set forth above, the above method allows for a greater response tothe memantine therapy of Alzheimer type dementia as compared to theresponse obtained with memantine alone. The method is based on asurprising finding in a limited but indicative clinical investigation inpatients with moderate Alzheimer-type dementia, 58% of whom were treatedwith memantine.

The above combined memantine/solifenacin treatment involves greater andlonger efficacy and less adverse effects by allowing the safe andtolerable administration of therapeutically effective, high-doses ofdonepezil. In particular, the treatment with donepezil according to thepresent invention is safe and effective, also in combination with otherpharmaceuticals, in treating patients in need of an acetylcholineesterase inhibitor, in particular dementias of the Alzheimer type on anormally once daily basis.

The aforementioned kits may help the physician, the relatives and thecaregiver to render the supply of the medicaments to the patient morecomfortable.

The pathologic conditions treated with the compositions and kits of thepresent invention include, but are not limited to, Alzheimer's disease,Parkinson's disease dementia, Lewy body dementia and other disorders ofhuman cognitive and neurobehavioral function that are treated, in part,by pharmaceuticals intended to augment brain acetylcholine-mediatedneurotransmission.

The therapeutic efficacy is measured by the degree to which cognitiveand other neurobehavioral disabilities associated with dementias of theAlzheimer type, as documented by the use of standard scales, arereduced.

The following examples illustrate the invention.

Example 1

Patients with moderate Alzheimer's disease were enrolled in a clinicaltrial to examine the efficacy of high doses of donepezil (enabled by theconcomitant administration of solifenacin) with or without memantine.The dose of solifenacin was fixed throughout the trial at 15 mg/day. Thedose of donepezil was titrated up to 40 mg per day, or to highesttolerated dose, whichever came first. To be enrolled, patients had tohave been treated with donepezil 10 mg per day for at least 12 weeks.Concomitant use of memantine was allowed, provided patients were treatedwith a stable dose of memantine for at least 8 weeks prior toenrollment, and providing the dose of memantine remained stablethroughout the trial.

A total of 26 evaluable patients were enrolled in the study, 11 malesand 15 females, mean age 74+8 years, and mean weight 74+18 kg. A totalof 15 patients were on concomitant memantine upon study entry andremained on the same dose of memantine throughout the study.

Patients received increasing doses of donepezil together with a fixeddose of solifenacin (15 mg per day). A total of 22 patients reached andmaintained the 40 mg/day dose of donepezil; 3 patients in thedonepezil+memantine group (20%) and 2 patients in the donepezil withoutmemantine group (18%) were not able to tolerate maximum allowed dose of40 mg/day of donepezil. Thus, there was no difference in the percentageof patients on memantine and patients off memantine in their ability totolerate high doses of donepezil.

Patients were tested on the ADAS-cog at study entry, when they reachedMaximum Tolerated Dose (MTD) of donepezil, and 4 weeks after reachingMTD.

Response on the ADAS-cog was defined versus baseline as either no changeor improvement. Four weeks after reaching their MTD, 73% of patients onmemantine and only 60% of patients not receiving concomitant memantinewere judged to be responders. These results show that unexpectedly,patients who were concomitantly treated with memantine had greaterimprovement with high doses of donepezil than patients receiving highdoses of donepezil without concomitant memantine.

Since improvement was judged versus baseline, at a time when patientswere either on or off memantine and remained that way for the durationof the trial, one would have expected any further increase in efficacyto be attributable only to the higher doses of donepezil. There shouldtherefore have been no difference in improvement between high dosedonepezil with memantine or without memantine. Yet, patients who wereconcomitantly treated with memantine had greater improvement with highdoses of donepezil than patients receiving high doses of donepezilwithout concomitant memantine.

Example 2

As a further approach to the result of the clinical trial of Example 1,after discarding the two best and the two worst responses to treatmentof the patients with and without memantine, it was observed as follows.

No Memantine Co-Treatment:

Case 1. An 88 year old woman with a baseline MMSE score of 20 declinedcognitively by 1.33 ADAS-cog points.Case 2. An 80 year old woman with a baseline MMSE score of 18 declinedby 3.65 points.Case 3. A 57 year old man with a baseline MMSE score of 20 declined by4.33 points.Case 4. A 74 year old woman with a baseline MMSE score of 19 declined by3.67 points Memantine co-treated: Case 1. A 63 year old man with abaseline MMSE score of 12 improved by −5.66 points.Case 2. An 87 woman with a baseline MMSE score of 16 improved by −7.33points at her maximum tolerated dose of 25 mg/day donepezil.Case 3. An 81 man with a baseline MMSE score of 20 improved by −8.67points.Case 4. A 75 year old woman with a baseline MMSE score of 17 improved by−4.34 points.

The substantially greater cognitive benefit occurring with high dose(median 40 mg/day) donepezil treatment (administered with solifenacin 15mg/day) in those also receiving standard dose memantine, compared withthose who did not receive memantine, surprisingly attained statisticalsignificance:

−6.5±0.95 versus 3.3±0.66, respectively; p<0.05).

The observed effect size in moderately severe AD patients is ofconspicuous clinical significance.

Example 3

Tablet containing 28 mg of memantine hydrochloride, formulated with apharmaceutical carrier in ER-formulation, and tablets containing 10 mgof solifenacin succinate, formulated with a pharmaceutical carrier inIR-formulation, are distributed in capsules as described in GB1,204,580, such that unit dosage forms each containing 28 mg ofmemantine hydrochloride in ER-formulation and 15 mg of solifenacinsuccinate in IR-formulation are prepared.

In the same manner, unit dosage forms each containing 28 mg of memantinehydrochloride formulated in admixture with a pharmaceutical carrier inan ER-formulation, tablets containing 15 mg of solifenacin succinateformulated with a pharmaceutical carrier in IR-formulation are prepared.

What is claimed is: 1.-5. (canceled)
 6. A method for the treatment of a hypocholinergic disorder, which comprises treating a patient in need of said treatment with an effective dose of a N-methyl-D-aspartate receptor antagonist Component (a) selected from the group consisting of memantine and pharmaceutical acceptable salts thereof and with an effective amount of a naAEA Component (b), in further combination with (c) donepezil or a pharmaceutically acceptable salt thereof, in an amount that is equivalent to from 10 mg to 92 mg of donepezil hydrochloride and; (d) solifenacin or a pharmaceutically acceptable salt thereof, in an amount that is equivalent to from 10 mg to 30 mg of solifenacin succinate.
 7. The method of claim 6, wherein said effective amount of memantine or a pharmaceutically acceptable salt thereof Component (a), is a daily dose that is equivalent to from 5 mg to 30 mg of memantine hydrochloride.
 8. The method of claim 6, wherein said Component (a) is a pharmaceutical composition in dosage unit form comprising said memantine or pharmaceutically acceptable salt thereof in an amount that is equivalent to from 5 mg to 30 mg of memantine hydrochloride, in admixture with a pharmaceutical carrier or vehicle; said Component (b) is a pharmaceutical composition in dosage unit form comprising a naAEA selected from the group consisting of alosetron and pharmaceutically acceptable salts and solvates thereof, in an amount (in alosetron) of from 0.25 mg to 6 mg; azasetron and pharmaceutically acceptable salts and solvates thereof, in an amount (in azasetron) of from 5 mg to 60 mg; dolasetron and pharmaceutically acceptable salts and solvates thereof, in an amount (in dolasetron) of from 25 mg to 600 mg; granisetron and pharmaceutically acceptable salts and solvates thereof, in an amount (in granisetron) of from 0.5 mg to 6 mg; ondansetron and pharmaceutically acceptable salts and solvates thereof, in an amount (in ondansetron) of from 2 mg to 64 mg; palonosetron and pharmaceutically acceptable salts and solvated thereof, in an amount (in palonosetron) of from 0.25 mg to 3 mg; ramosetron and pharmaceutically acceptable salts and solvates thereof, in an amount (in ramosetron) of from 0.0125 mg to 0.3 mg; tropisetron and pharmaceutically acceptable salts and solvates thereof, in an amount of from 2.5 mg to 30 mg; domperidone and pharmaceutically acceptable salts and solvates thereof, in an amount (in domperidone) of from 5 mg to 60 mg; haloperidol, in an amount of from 0.5 mg to 60 mg; chlorpromazine and pharmaceutically acceptable salts and solvates thereof, in an amount (in chlorpromazine) of from 12.5 mg to 600 mg; prochlorperazine and pharmaceutically acceptable salts and solvates thereof, in an amount (in prochlorperazine) of from 2.5 mg to 30 mg; metoclopramide and pharmaceutically acceptable salts and solvates thereof, in an amount (in metoclopramide) of from 5 mg to 60 mg; bromopride and pharmaceutically acceptable salts and solvates thereof, in an amount (in bromopride) of from 5 mg to 60 mg; clebopride and pharmaceutically acceptable salts and solvates thereof, in an amount (in clebopride) of from 0.25 mg to 3 mg; levosulpiride, in an amount of from 12.5 mg to 600 mg; alizapride and pharmaceutically acceptable salts thereof, in an amount (in alizapride) of from 25 mg to 300 mg; trimethobenzamide and pharmaceutically acceptable salts thereof, in an amount (in trimethobenzamide) of from 50 mg to 600 mg; meclizine (also called meclozine) and pharmaceutically acceptable salts and solvates thereof, in an amount (in meclizine) of from 6.25 mg to 300 mg; promethazine and pharmaceutically acceptable salts and solvates thereof, in an amount (in promethazine) of from 12.5 mg to 150 mg; dronabinol in an amount of from 1.25 mg to 60 mg; nabilone, in an amount of from 0.5 mg to 6 mg; aprepitant, in an amount of from 20 mg to 750 mg; netupitant, in an amount of from 150 mg to 1800 mg; rolapitant, in an amount of from 30 mg to 360 mg; and casopitant, in an amount of from 25 mg to 300 mg, in admixture with a pharmaceutical carrier or vehicle; said Component (c) is a pharmaceutical composition in dosage unit form comprising donepezil or pharmaceutically acceptable salt thereof in an amount that is equivalent to from 20 mg to 92 mg of donepezil hydrochloride, in admixture with a pharmaceutical carrier; and said Component (d) is a pharmaceutical composition in dosage unit form comprising solifenacin or a pharmaceutically acceptable salt thereof, in a pharmaceutical composition comprising said solifenacin or pharmaceutically acceptable salt thereof in an amount that is equivalent to from 10 mg to 30 mg of solifenacin succinate, in admixture with a pharmaceutical or vehicle.
 9. The method of claim 8, wherein said Component (a) is a pharmaceutical composition comprising said memantine hydrochloride in an amount of from 7 mg to 28 mg, in admixture with a pharmaceutical carrier in an ER formulation; and said Components (c) and (d) are in a fixed-dose (c/d) combination consisting of a pharmaceutical composition in dosage unit form comprising (c) donepezil hydrochloride, in an amount of from 10 mg to 92 mg; and (d) solifenacin succinate, in a pharmaceutical composition comprising said solifenacin succinate in an amount of from 10 mg to 30 mg, in admixture with a pharmaceutical carrier or vehicle, in an IR-formulation.
 10. The method of claim 9 wherein, in said fixed-dose combination (c/d) said Component (c) is donepezil hydrochloride, in an amount of from 10 mg to 50 mg; and said Component (d) is solifenacin succinate, in an amount of 15 mg. 11.-26. (canceled) 